In Silico Study of Argan Oil Metabolites: Evaluation of Their Potential to Inhibit Key Receptors Activated by Excessive Alcohol Consumption and Involved in Cell Death

In Silico Study of Argan Oil Metabolites: Evaluation of Their Potential to Inhibit Key Receptors Activated by Excessive Alcohol Consumption and Involved in Cell Death | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article In Silico Study of Argan Oil Metabolites: Evaluation of Their Potential to Inhibit Key Receptors Activated by Excessive Alcohol Consumption and Involved in Cell Death Ayoub Bekkouch, Oussama Bekkouch, Anas Ziani, Nour E. Bentouhami, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6049168/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Excessive alcohol consumption is a well-established cause of liver injury and neurodegeneration, driven by oxidative stress, inflammation, and apoptosis. This study explores the potential of Argania spinosa (argan oil) metabolites as natural inhibitors of key receptors involved in alcohol-induced cellular damage: NOX4 (NADPH Oxidase 4), PARP (Poly ADP-ribose Polymerase), and CCR2 (C-C Motif Chemokine Receptor 2). Using in silico approaches, including molecular docking, ADMET analysis, and molecular dynamics simulations, we systematically evaluated the interactions between twenty previously reported argan oil metabolites and these receptors. Among the analyzed compounds, spinasterol emerged as the most promising bioactive molecule, demonstrating high binding affinity and structural stability within the receptor active sites. Molecular interaction analysis revealed strong hydrophobic interactions, π-π stacking, and hydrogen bonding, contributing to receptor inhibition. These findings suggest that spinasterol could modulate inflammatory and oxidative pathways, reducing alcohol-induced cellular stress. This study underscores the potential of argan oil metabolites as natural therapeutic agents for preventing and mitigating alcohol-related pathologies. Future in vitro and in vivo investigations are necessary to validate these computational results and explore the translational potential of these compounds in clinical settings. The findings contribute to advancing plant-based drug discovery and natural pharmacological interventions for alcohol-induced disorders. argan oil metabolites cell death NOX-4 PARP CCR2 ADME analysis Docking Molecular dynamic Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Excessive alcohol consumption has long been recognized as a major and significant cause of liver cell injury (Peacock et al., 2018; World Health Organization, 2018) . The intricate pathophysiology of alcohol-induced liver disease is known to be quite complex, as it involves numerous biological pathways and mechanisms. The analysis of new therapeutic agents, such as the compounds derived from argan oil along with its various metabolites, is emerging as a promising approach for the discovery and development of new drugs that could potentially aid in mitigating liver damage. A thorough review of the current status of drug modeling studies focused on addressing the impacts of alcohol and its diverse pathophysiologies, however, reveals that many studies conducted thus far are primarily limited to the modeling of ligands. Nevertheless, research efforts concentrating on the identification and characterization of new bioactive molecules derived from argan oil and its metabolites and judging their potential effectiveness to inhibit key receptors that get activated due to excessive alcohol consumption (El Monfalouti et al., 2010; El Mostafi et al., 2020) , which leads to cellular death, have not yet been thoroughly described in the existing literature. Therefore, this study aimed to systematically screen and rigorously evaluate the potential molecular interactions of twenty previously reported argan oil metabolites against several specific protein receptors known to be involved in alcohol-induced pathophysiological processes. Docking studies were performed using two distinct genome-wide docking approaches, and the resultant score functions were meticulously analyzed to ensure accuracy and reliability. Highly scored putative drug molecules, identified as a result of docking studies, were subsequently subjected to molecular dynamics simulations to assess the structural stability of the resulting complexes over time. The comprehensive screening demonstrated that the biotransformation of argan oil compounds yielded a variety of molecules that exhibited the capability to effectively inhibit key receptors associated with alcohol metabolism. (Huey et al., 2012; Morris et al., 2008) These promising results may promote the argan oil compound metabolites as potentially valuable components in the prevention or treatment of various alcohol-induced pathologies and liver diseases. 1.1. Background and Rationale Excessive alcohol consumption, recognized for its detrimental health effects, is a significant contributor to cellular damage, including cell death, which poses substantial medical concerns (GAO et al., 2022) . This issue extends beyond individual health, representing a critical public health challenge that necessitates focused attention. As Argania spinosa (argan oil) and its bioactive metabolites gain traction in nutrition and health domains (Adlouni, 2010) , it becomes increasingly vital to explore the potential of these compounds in alleviating the damaging impacts of alcohol on human cells and tissues (Charrouf & Guillaume, 2008; Khong & Chan, 2022) This study primarily aims to bridge the notable research gap concerning this issue through the application of advanced in silico methodologies. Techniques such as molecular docking and molecular dynamics simulations will enable the detailed modeling of intricate interactions between argan oil metabolites and the cell death signaling pathways disrupted by alcohol exposure. By enhancing our understanding of these complex interactions, we aim to better assess the potential protective effects conferred by argan oil metabolites. Additionally, this research will provide scientific evidence illustrating how these metabolites may mitigate the cellular damage induced by alcohol. Ultimately, this work aspires to lay a relevant and robust scientific foundation that supports future investigations within a rigorous research framework, paving the path for the development of new preventive and therapeutic strategies against alcohol-induced cellular damage.Historically, argan oil has been celebrated for its balsamic and nourishing properties(Adlouni, 2010; Cherki et al., 2006; El Monfalouti et al., 2010). Within the traditional pharmacopoeia of southwestern Morocco, argan oil has been utilized to address various ailments and is renowned for its ability to promote energy, warmth, and vitality. Despite the extensive identification of various metabolites derived from argan oil, their interactions with key receptors implicated in the pathology of excessive alcohol consumption remain poorly understood. Therefore, the primary goal of this investigation is to examine the interactions of these metabolites with specific receptors associated with these disorders (Bekkouch et al., 2024; Bellamma et al., 2023) , which are anticipated to influence certain cell death pathways. A comprehensive search for argan oil metabolites was conducted utilizing multiple databases for identification purposes. 1.2. Aim and Objectives The ambitions of this research revolve around a comprehensive understanding of the effects of argan oil metabolites, with a particular focus on its richness in molecules. Our main emphasis is on the unsaponifiable fraction, specifically examining those molecules with the highest content in relation to the signaling pathways involved in cell death. This specific focus is justified in the context of alcohol consumption, as we choose enzymes that are directly implicated in this cellular process(Li et al., 2022; Xie et al., 2020). To explore these interactions, we employ advanced in silico methods, such as molecular docking and molecular dynamics. It is also crucial to rigorously assess how these rich metabolites interact with the signaling pathways disrupted by alcohol, while examining the potential consequences of these interactions on human health. Furthermore, our approach aims to identify specific molecular targets that play a fundamental role in these mechanisms, thereby paving the way for novel therapeutic avenues in medicine and pharmacology. By adopting this strategy, we hope to not only enrich existing scientific knowledge but also establish a solid foundation for future applications that could revolutionize prevention and treatment strategies for alcohol-related cellular damage. chemical composition of argan oil Table 1 Argan oil composition Component Concentration Main Roles Source Unsaturated Fatty Acids ~ 80% Cellular regeneration, reduction of inflammation. INRA Morocco, Cahiers Agricultures Oleic Acid (Omega-9) 45–50% Cardiovascular health, membrane flexibility. INRA Morocco Linoleic Acid (Omega-6) 30–35% Essential for immune and skin functions. INRA Morocco Polyphenols Notable presence Neutralization of ROS, antioxidant properties. INRA Morocco Tocopherols (Vitamin E) ~ 620 mg/kg Protection of cellular membranes from oxidative damage. Cahiers Agricultures Sterols (Schottenol, Spinasterol) Present Reduction of inflammation, tissue regeneration. INRA Morocco Squalene ~ 0.3–0.4% Powerful antioxidant, protection against oxidative damage. INRA Morocco Minerals (Potassium, Magnesium) Present Enzymatic and electrolyte regulation. INRA Morocco Volatile Compounds Traces Contribution to aroma and sensory quality of the oil. INRA Morocco Argan oil from Morocco is a natural treasure with a chemical composition that varies based on the extraction method employed. The most common technique involves cold pressing the argan nuts, a traditional method that preserves bioactive compounds while preventing the degradation of fatty acids and antioxidants. This approach ensures the production of a high-quality oil, rich in essential nutrients. Comprehensive analyses of argan oil's chemical composition are conducted using advanced chromatographic techniques. For instance, gas chromatography coupled with mass spectrometry (GC-MS) is employed to identify and quantify fatty acids and sterols. The levels of tocopherols (vitamin E) are frequently measured using high-performance liquid chromatography (HPLC), while spectrophotometric methods quantify polyphenols. Research findings reveal that argan oil is particularly abundant in fatty acids, mainly oleic acid (omega-9) and linoleic acid (omega-6), which collectively account for over 70% of its structure. This high concentration of unsaturated fatty acids imparts moisturizing and nourishing properties to the oil, making it ideal for skin and hair care while also promoting cardiovascular health. Additionally, although present in smaller amounts, palmitic acid (12%) and stearic acid (6%) contribute to the oil's stability and its diverse applications in cosmetics (Abbassi et al., 2014; Adlouni, 2010; Charrouf & Guillaume, 2008; El Monfalouti et al., 2010; Menni et al., 2020). The oil’s high tocopherol concentration (ranging from 600 to 900 mg/kg) is a significant asset for its antioxidant properties, playing a crucial role in protecting cells from oxidative stress and slowing skin aging. Moreover, the sterolic fraction, primarily composed of schottenol (46–49%) and spinasterol (39–42%), enhances the anti-inflammatory and cholesterol-lowering effects of the oil, justifying its use in the prevention of metabolic disorders. Although polyphenols are present in relatively lower quantities, they bestow anti-inflammatory and antimicrobial properties to the oil while contributing to its oxidative stability. The unsaponifiable fraction, representing between 0.34% and 0.79% of the total composition, includes essential bioactive compounds such as sterols and tocopherols, which reinforce the therapeutic and cosmetic benefits of argan oil (Charrouf & Guillaume, 2010; Hilali et al., 2005; Kharbach et al., 2019). In recent years, natural components toxic to humans in high doses and mixtures have been tested in in vivo or in vitro models as promising treatments or protectants against organ injuries caused by various factors. For instance, some phenolic compounds like ellagic acid, curcumin, catechin, and pyrogallol derived from « A. spinosa » exhibit hepatoprotective effects due to their anti-inflammatory and pro-antioxidant activities. Most studies have primarily focused on the potential effects and action mechanisms of « A. spinosa » and its bioactive compounds when used in isolation. However, given that a multitude of bioactive metabolites from A. spinosa can coexist in tissues, additional research has explored the intricate mechanisms associated with these metabolites. Potentiel effect on health : Argan oil emerges as a particularly rich source of various bioactive compounds, offering numerous health benefits for human well-being. It is notably high in unsaturated fatty acids, including omega-6 and omega-9 fatty acids. These essential fatty acids are vital for our body as they play a crucial role in lowering "bad" LDL cholesterol while increasing "good" HDL cholesterol. This action aids in enhancing overall cardiovascular health and reducing blood pressure. Furthermore, tocopherols, or vitamin E, present in argan oil, act as powerful antioxidants. These important compounds protect cells from oxidative stress, a harmful process, thus contributing to the prevention of skin aging and providing neuronal protection, emphasizing their significant role in neuroprotection. Additionally, the presence of polyphenols in this precious oil endows it with both anti-inflammatory and antimicrobial properties. These attributes enhance insulin sensitivity and help mitigate the risk of developing type 2 diabetes. Plant sterols, such as schottenol and spinasterol, also play a role by aiding in the reduction of cholesterol absorption in the intestine and may even exhibit potential anticancer effects. Squalene, another remarkable component of argan oil, helps shield the skin from various external aggressors while playing a key role in improving skin hydration and potentially alleviating the appearance of precancerous lesions. Alongside its well-documented anti-aging effects and hepatoprotective properties, argan oil may also significantly reduce neurotoxic effects associated with excessive alcohol consumption. Despite these exceptional qualities, further clinical studies are necessary to validate these findings in humans, as the myriad benefits make argan oil an invaluable ally in the prevention of various chronic diseases (Adlouni, 2010; Berrada et al., 2000; Charrouf & Guillaume, 2008, 2010; Cherki et al., 2006; El Monfalouti et al., 2010) Alcohol and cell death : PARP, NOX4 et CCR2 Mechanisms of Alcohol Toxicity : The significance of research into molecular pathways as therapeutic targets is underscored by the devastating repercussions of excessive and chronic alcohol consumption. This behavior is a crucial factor in cellular dysfunction and tissue pathologies, particularly in vital organs such as the brain and liver. The toxic effects of alcohol are manifested through complex biological processes that undermine normal tissue function. Central to this toxicity is the metabolism of ethanol, which converts into acetaldehyde, a highly reactive and toxic metabolite (Burton, 2005 ; Nakamura et al., 2003 ; Oba et al., 2008 ; Serio & Gudas, 2020 ; Setshedi et al., 2010 ; Svegliati-Baroni et al., 2001). Acetaldehyde inflicts direct damage on liver cells, resulting in considerable cellular deterioration. Concurrently, alcohol promotes the excessive production of free radicals while depleting antioxidant levels in the liver, thereby heightening oxidative stress and its detrimental effects (Fan et al., 2022; GAO et al., 2022; Yang et al., 2012; X. Zhang et al., 2004) . Additionally, it triggers a robust inflammatory response, worsening existing injuries and tissue damage. These interconnected mechanisms are pivotal in the pathogenesis of various liver diseases, including fatty liver, fibrosis, and cirrhosis. Three critical molecules, namely PARP (Poly(ADP-ribose) polymerase), NOX4 (NADPH Oxidase 4), and CCR2 (C-C Motif Chemokine Receptor 2), play essential roles in these pathological processes. Their involvement in alcohol-induced cell death intensifies neuronal and hepatic damage (Tang et al., 2022) . Therefore, it is crucial to investigate these molecular targets in the context of analyzing the effects of argan oil on cell death, especially concerning the alarming issue of excessive alcohol consumption, in order to develop therapeutic strategies aimed at mitigating these harmful health effects. PARP : Poly(ADP-ribose) Polymérase PARP is an enzyme activated in response to DNA breaks caused by oxidative stress, often amplified by alcohol consumption. A study by Zhou et al. (2003) demonstrated that excessive activation of PARP can lead to energy depletion and neuronal damage in animal models subjected to oxidative stress. Similarly, Czaja (2015) showed that inhibiting PARP significantly reduces liver inflammation and cellular damage induced by alcohol. This enzyme repairs DNA damage by consuming NAD⁺, an essential cofactor for metabolic reactions. However, excessive PARP activation has deleterious effects (Chen et al.,2016.; Teng et al., 2016) : It depletes NAD⁺ and ATP reserves, leading to a fatal energy deficit for cells. It exacerbates mitochondrial dysfunction, worsening neuronal damage. It promotes inflammation by activating pro-inflammatory mediators. In the liver, PARP contributes to the progression of alcoholic steatohepatitis, while in the brain, its excessive activation is associated with oxidative stress-related neuronal injury. Inhibition of PARP, using compounds like olaparib, has shown protective potential against alcohol-related damage by reducing energy depletion and inflammation. (Li et al., 2022 ; Zhang et al., 2015.) NOX4 : NADPH Oxidase 4 NOX4 is a key enzyme in the production of reactive oxygen species (ROS), playing a central role in alcohol-induced oxidative stress. Studies have shown that the activation of NOX4 in hepatic cells can increase ROS levels by 200%, causing significant damage to lipids and membrane proteins. Furthermore, NOX4 is highly expressed in neurons under chronic alcohol exposure, contributing to neuronal degeneration and amplifying neuroinflammation. This enzyme is expressed in hepatocytes, neurons, and glial cells, where it is highly stimulated by alcohol exposure. Production of ROS: NOX4 generates reactive oxygen species (ROS) that damage lipids, proteins, and DNA , triggering apoptotic and ferroptotic processes. Role in alcohol-induced lesions: o In the liver, NOX4 promotes fibrosis and the progression of alcoholic steatosis. o In the brain, it contributes to neuronal degeneration and neuroinflammation. Therapeutic targets: Specific NOX4 inhibitors, such as GKT137831 , have demonstrated significant reductions in oxidative and inflammatory damage in experimental models. CCR2 : C-C Motif Chemokine Receptor 2 CCR2 is a chemokine receptor involved in recruiting immune cells to damaged tissues. This receptor is activated by ligands like CCL2 (also known as MCP-1 ), which enhance the attraction of monocytes, macrophages, and T cells to inflammatory sites. Upon activation, CCR2 initiates intracellular signaling cascades involving G-proteins that stimulate pro-inflammatory pathways, including the production of cytokines such as TNF-α and IL-6. Additionally, it modulates the activation of microglial cells in the brain, further amplifying neuroinflammation.(Lowe et al., 2020; Ren et al., 2017; K. Zhang & Luo, 2019) In the liver, CCR2 plays a critical role by promoting the accumulation of pro-inflammatory macrophages and exacerbating liver damage associated with fibrosis and alcoholic steatohepatitis. Under the influence of alcohol, CCR2 expression increases in macrophages, microglia, and endothelial cells, worsening chronic inflammation. We investigate the effects of alcohol on the expression of proteins implicated in these carcinogenic processes across the digestive organs and the liver. A literature review identified several proteins previously considered as drug targets: hydroxy-carboxylic acid receptor (à G-protein-coupled receptor), metabotropic glutamate receptor, excitatory amino acid transporter, muscarinic acetylcholine receptors, and histone deacetylase. Overactivation of these receptors leads to decreased glucose consumption and reduced lipolysis. Of particular relevance to the central nervous system ( CNS ) is the key role of these receptors in facilitating synaptic plasticity and memory formation, where excessive activation can result in excitotoxicity due to increased calcium influx. Inflammatory Mechanisms : - CCR2 promotes the infiltration of monocytes and immune cells into damaged tissues. - It stimulates the release of pro-inflammatory cytokines, such as TNF-α and IL-6 , which exacerbate cellular damage. Effects on Alcohol-Related Pathologies: - In the liver, CCR2 plays a pivotal role in the progression of alcoholic steatohepatitis by enhancing inflammation and fibrosis. - In the brain, CCR2 contributes to chronic neuroinflammation, worsening cognitive disorders associated with alcoholism. Potential Therapies: Inhibition of CCR2 (for example, via cenicriviroc) shows promise for reducing inflammatory damage in the context of alcoholism. Interactions Between PARP, NOX4 , and CCR2 : These three molecules act synergistically to establish a vicious cycle that amplifies the toxic effects of alcohol: - NOX 4 generates reactive oxygen species (ROS) which damage DNA, subsequently activating PARP . - Excessive activation of PARP leads to cellular energy depletion, increasing mitochondrial dysfunction and exacerbating cell death. (Zhang et al., 2018) -Concurrently, CCR2 intensifies the infiltration of immune cells and the release of cytokines, worsening inflammation and oxidative damage. This interconnection renders these molecules particularly attractive as combined therapeutic targets for interrupting the pathological process. Therapeutic Strategies: 1. PARP Inhibitors: Aim to reduce energy depletion and prevent neuronal and hepatic damage. (Chen et al., n.d.) 2. NOX4 Inhibitors: Seek to limit ROS production and alleviate oxidative stress. (Xie et al., 2020) 3. CCR2 Inhibitors: Focus on blocking the infiltration of inflammatory cells and reducing chronic inflammation. (K. Zhang et al., 2018) 4. Combined Approaches: An integrated therapy targeting PARP, NOX4 , and CCR2 could provide synergistic protection against alcohol-induced damage. Alcohol induces cell death through complex mechanisms involving PARP, NOX4 , and CCR2 , which work together to amplify oxidative stress, inflammation, and energy dysfunction. These interactions extend beyond mere cellular toxicity, paving the way for innovative therapeutic strategies. Inhibitors targeting these molecules have the potential to disrupt the pathological cascades responsible for tissue damage. Future research may prioritize clinical trials combining these inhibitors with other innovative approaches, assessing their effectiveness in mitigating neurodegenerative and hepatic complications. A more profound understanding of molecular interaction networks in these contexts could revolutionize the management of patients affected by alcoholism. Insights into these interactions offer promising prospects for developing targeted and combined therapies capable of preventing or alleviating alcohol-induced tissue injuries. Such strategies could transform the management of complications associated with alcohol use and enhance the quality of life for affected individuals. Additionally, CCR2 is crucial for understanding ethanol-induced excitotoxicity, serving as a primary transporter of excitatory amino acids in the brain and working alongside various other proteins to facilitate glutamate transport and prevent toxic overstimulation of neurotransmitter pathways. Alcohol disrupts this function, potentially worsening receptor interactions associated with the adverse neurobehavioral effects of fetal alcohol exposure. In the case of muscarinic receptors, excessive activation can lead to central nervous system suppression. Furthermore, the enzyme responsible for deacetylating histones surrounding oncogenes with carcinogenic properties is significantly inhibited, resulting in hyperacetylation and diminished gene expression. The Importance of Research on Molecular Pathways as Therapeutic Targets : Investigations into molecular pathways such as PARP, NOX4, and CCR2 as therapeutic targets are gaining increasing attention in the biomedical field, given their roles in complex pathological processes. These molecules are central to the pathophysiological mechanisms associated with cell death, significantly manifested through the amplification of oxidative stress, chronic inflammation, and mitochondrial dysfunction. A targeted approach toward these pathways could facilitate the development of innovative therapeutic strategies, particularly aimed at preventing or alleviating cellular damage caused by complex pathologies, such as those often linked to excessive alcohol consumption and its detrimental effects on the body. Therapeutic Potential of Argan Oil Metabolites, widely recognized for its exceptional richness in bioactive compounds such as polyphenols, tocopherols, and unsaturated fatty acids, represents a natural resource of notable interest for its unique protective properties against alcohol-induced damage (Bekkouch et al., 2025) . These metabolites are distinguished by their well-established antioxidant and anti-inflammatory characteristics across various contexts, which could be leveraged to modulate the activities of PARP, NOX4, and CCR2 in a targeted manner. While the effectiveness of these compounds in inhibiting these molecular targets still requires thorough exploration in specific preclinical models, their potential truly opens up promising avenues for the development of novel naturally-derived therapeutic approaches, there by providing viable solutions to complex disorders. In Silico Methodology in Biology (ADME, AutoDock, Schrödinger) 1. SwissADME : Is an innovative online tool developed by the Swiss Institute of Bioinformatics (SIB) to predict a variety of pharmacological and pharmacokinetic properties relevant to bioactive molecules. Fully free of charge and easily accessible, it has rapidly gained recognition as a preferred resource in the fields of medicinal chemistry and pharmacology for evaluating the essential characteristics related to absorption, distribution, metabolism, excretion (ADME), and potential toxicity (ADMET) of diverse chemical compounds. By simply inputting a molecular structur either in SMILES format or by utilizing a convenient drawing interface—SwissADME generates precise and comprehensive analyses of several crucial parameters. This powerful tool facilitates a thorough evaluation of absorption characteristics, including essential metrics like water solubility and intestinal permeability—two critical elements needed to predict the efficacy and functionality of molecules when administered via oral routes. Additionally, it supplies vital data regarding pharmacokinetic properties, such as the ability of various molecules to cross the blood-brain barrier (BBB) and their potential role as substrates for P-glycoprotein (P-gp), both significantly influencing their overall bioavailability and effectiveness. SwissADME features detailed "drug-likeness" analyses based on well-established rules of Lipinski, Ghose, Veber, and other established criteria, enabling researchers to conduct compliance assessments of a molecule with industry-standard drug characteristics. Moreover, the tool identifies potential interactions with cytochrome P450 enzymes, which are critically important for understanding the complex metabolic pathways of various molecules and effectively predicting possible drug-drug interactions that may arise within biological systems. While SwissADME does not provide a comprehensive toxicological evaluation, it allows users to detect alerts based on the physicochemical properties of the examined molecules. By seamlessly combining sophisticated predictive models with rigorous and precise calculations, SwissADME proves to be an indispensable instrument for the initial stages of drug design and discovery. Its advanced capacity to reduce costs and significantly shorten the timelines often associated with the development of therapeutic molecules renders it an invaluable resource for optimizing therapeutic candidates and accelerating research advancements in the complex field of pharmacology. (Bekkouch et al., 2025; Zekri et al., n.d.) 2. Docking : The utilization of AutoDock Vina for ligand-receptor docking simulations is structured around a methodical approach encompassing several essential and interrelated steps. Initially, it is crucial to diligently download and install the necessary software, including both AutoDock Vina and AutoDockTools (ADT), carefully adhering to the comprehensive guidelines outlined on the official website. The structure preparation phase begins with the importing of the target macromolecule, which is often sourced from the reputable Protein Data Bank (PDB), alongside the ligands of interest for the docking studies. Within ADT, the macromolecule structure is meticulously cleaned by removing extraneous water molecules, adding polar hydrogens, and assigning Gasteiger partial charges, before saving it in the specialized PDBQT format tailored for AutoDock use. Each ligand is similarly imported and subjected to rigorous processing, encompassing the addition of hydrogens and proper assignment of partial charges. Rotatable bonds within each ligand are identified thoughtfully to determine the root atom around which flexibility is permitted during the docking process, after which every ligand is saved in the required PDBQT format, ensuring compatibility with the docking software. Next, the docking box is configured adequately to define the spatial area of potential interaction between the ligands and the receptor. This necessitates the careful specification of dimensions and positional coordinates of the grid, supplemented by the number of points allocated in each spatial direction and the associated spacing between them, typically set at 0.375 Å for optimal resolution. A docking parameter file (DPF) is subsequently generated to establish the various search algorithm parameters. These may include a hybrid genetic algorithm coupled with a local search (GA-LS) approach to yield enhanced accuracy for the docking results. Parameters outlined within the DPF encompass the maximum permissible number of energy evaluations alongside the required search cycles. Once the DPF file is finalized and carefully reviewed, the energy map undergoes calculation through the AutoGrid utility, followed by the docking process itself using the AutoDock Vina software, executed via terminal commands. Results of the docking are meticulously analyzed from the generated log file, wherein the binding affinity scores of the ligand-receptor complexes are examined in detail. These docking results are subsequently visualized in 3D using ADT, where various conformations are clustered systematically according to their respective binding energy, with the lowest scores indicating the best affinity outcomes. A comprehensive final evaluation is conducted to validate the convergence of the simulations utilizing various clustering methods and to strategically select the conformation that exhibits the best stability alongside the most relevant interactions with the receptor's active site. (Huey et al., 2012; Morris et al., 2008) 3. Molecular Dynamics : In this detailed study, molecular dynamics methodology was rigorously employed to refine the outcomes of the docking results obtained previously. The software used specifically for these intricate simulations is Schrödinger. Molecular structures were diligently prepared with the help of the Protein Preparation Wizard tool, which allows for the precise adjustment of protonation states, the addition of missing ions, correction of hydrogen bonds, and thorough structural optimizations that are critical for obtaining accurate simulations. Ligands were processed via the LigPrep module, ensuring the selection of optimal conformations that would contribute to the reliability of the overall study. Molecular dynamics simulations were systematically conducted using the powerful Desmond simulation engine, over extensive periods of 100 nanoseconds within an explicitly solvated environment utilizing the TIP3P solvent model, carefully maintaining isotonic conditions within an NPT ensemble (constant pressure and temperature) throughout the simulation procedure. The temperature was stabilized meticulously at 300 K and the pressure at 1 atm using the Nose-Hoover thermostat algorithm and the Martyna-Tobias-Klein barostat techniques, which are essential for maintaining the integrity of the molecular environment. Protein-ligand interactions were thoroughly explored using the advanced Simulation Interaction Diagram tool, which allowed for in-depth analysis of the evolution of hydrogen bonds, hydrophobic interactions, and binding energies over the course of the simulation timeline. The analysis of results gleaned from these molecular dynamics simulations revealed the stability of the formed complexes by examining RMSD (Root Mean Square Deviation) fluctuations and the consistency of critical interactions throughout the total simulated period, providing valuable insights into the dynamics of the ligand-receptor binding process. (Bai et al., 2023; Bekkouch et al., 2024; Hadi et al., 2023; Huey et al., 2012; Morris et al., 2008) Selection of Bioactive Compounds from Argan Oil : The meticulous selection of bioactive molecules found within the renowned argan oil, such as tocopherols, spinasterol, schottenol, and ferulic acid, is predicated not only on their notable concentrations within this valuable and highly sought-after oil but also on their remarkable synergistic properties that complement one another in a harmonious manner (Charrouf & Guillaume, 2008; El Abbassi et al., 2014; Kharbach et al., 2019). Furthermore, these compounds exhibit the capacity to directly target fundamental pathological mechanisms that are associated with the significant damages inflicted by alcohol consumption. Tocopherols, which are notably abundant in argan oil, serve as potent antioxidants with the critical ability to safeguard cell membranes from the harmful effects of lipid oxidation, which is often induced by the presence of free radicals. This protective mechanism proves to be crucial in addressing the cellular toxicity linked to alcohol exposure. In addition, spinasterol and schottenol, whose concentrations in argan oil are also quite significant, exhibit valuable anti-inflammatory properties by effectively modulating the secretion of pro-inflammatory cytokines while supporting essential cellular regeneration. This functionality is particularly important for alleviating injuries that can adversely affect not just the liver but also the nervous system. Ferulic acid, another major polyphenol that is found in abundance within argan oil, plays a pivotal role in negating reactive oxygen species (ROS)(Charrouf & Guillaume, 2008; Drissi et al., 2004; Gharby et al., 2011; Khong & Chan, 2022). This action effectively assists in preventing oxidative damage to vital cellular components such as DNA, proteins, and lipids. The exceptional richness of argan oil in these diverse bioactive components significantly enhances their relevance as a strategic selection for the current study, which aims to further delve into their potential effects. By collectively addressing oxidative stress, chronic inflammation, and mitochondrial dysfunctions that can arise, these bioactive molecules offer a comprehensive and integrated approach toward mitigating the negative consequences of excessive alcohol consumption on human health. This judicious selection of bioactive candidates is thus firmly substantiated by their well-documented efficacy in a variety of experimental models that focus on oxidative stress and inflammation. In addition, their remarkably high concentrations in argan oil position these compounds as particularly promising candidates for the development of innovative natural therapeutic applications. Such applications could provide genuine solutions to the pressing public health challenges posed by alcohol-related damage, thereby enhancing the overall well-being of individuals affected by excessive alcohol consumption and its associated complications. Résults and discussion In Silico Analysis of ADMET Properties of Argania spinosa Metabolites: Potential for Drug Developmen : The efficacy of a drug is largely determined by its absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, which can greatly limit its clinical application and overall therapeutic effectiveness (Daina et al., 2017) . Pharmacokinetics presents a major challenge in the development of new drugs, particularly due to the high costs associated with experimental testing and lengthy timelines required for such investigations. In this context, our comprehensive study employs advanced in silico approaches to meticulously evaluate the ADMET properties and assess the therapeutic potential of Argania spinosa metabolites as promising candidates for future drug development. Our detailed analysis encompasses various critical parameters, including in-depth evaluation of physicochemical characteristics, absorption profiles, distribution capabilities, metabolism pathways, excretion rates, and potential adverse effects, all systematically applied to compounds numbered from 1 to 8 as listed in Table 2. To ensure full compliance with established pharmaceutical standards, which are crucial for any potential drug entity, Lipinski’s Rule of Five was meticulously utilized during our assessment. This foundational rule specifies essential criteria, such as having fewer than 5 hydrogen bond donors, fewer than 10 hydrogen bond acceptors, a molecular weight (MW) of less than 500 Da, and a logP (MLOGP) not exceeding 4.15. Notably, every single analyzed phytoconstituent meets these fundamental criteria, indicating their promising oral bioavailability, which is further supported by an impressive average score of 0.55. Furthermore, concerning solubility, the compounds exhibit satisfactory aqueous solubility with logS values ranging between − 4 and 0, reflecting their considerable ability to dissolve effectively in a physiological environment conducive to human use. The absorption results reveal a compelling narrative, as all compounds exhibit high permeability across Caco-2 cells, indicating a strong intestinal absorption capacity in humans, which is essential for any potential oral drug. No substrate activity for P-glycoprotein was observed among the tested compounds; however, it is noteworthy that all compounds, with the sole exception of α-tocopherol, displayed inhibition of P-glycoproteins P1 and P2. Concerning distribution, the apparent volume of distribution (VDss) values suggest very good plasma distribution characteristics for the compounds evaluated. Both α and β-tocopherols appear particularly well-suited to effectively crossing the blood-brain barrier, endowing them with significant therapeutic potential in various neuroprotective strategies that merit further investigation. The metabolism analysis, conducted with precision, indicated no significant interactions with critical cytochrome P450 enzymes, including the isoenzymes CYP2D6, CYP1A2, CYP2C9, and CYP3A4, both when evaluated as substrates and inhibitors. This lack of interaction with major metabolic pathways underscores the safety profile and pharmacokinetic compatibility of these metabolites as potential therapeutic agents. Overall, the findings of this study point towards the promising future of Argania spinosa metabolites in drug development, effectively highlighting their significant therapeutic benefits alongside favorable pharmacokinetic properties. Table 3 ADMET profile1(α-tochopherol, 2 β-tochopherol, 3 γ-tochopherol, 4 spinasterol; 5-schottenol, 6 ferulic acid , (Bekkouch et al., 2024) Compounds 1 2 3 4 5 6 Drug- likeness Lipinski’s rule of five Yes Yes Yes Yes Yes yes Bioavailability Score 0.55 0.55 0.55 0.55 0.55 0.85 Water Solubility -6.901 -7.417 - 7.602 -6.773 -6.682 -2.817 Caco2 Permeability 1.345 1.73 1.458 1.201 1.213 0.176 Intestinal Absorption 89.782 89.452 90.43 94.464 94.97 93.685 Skin Permeability -2.683 -2.709 -2.62 -2.783 -2.783 -2.72 P-glycoprotein Substrate No No No No No No P-glycoprotein- 1 Inhibitor No Yes Yes Yes Yes No P-glycoprotein- 2 Inhibitor Yes Yes Yes Yes Yes No VDss (human) 0.709 0.946 0.732 0.193 0.178 -1.367 Distribution BBB Permeability 0.876 0.915 0.739 0.781 0.771 -0.239 CNS Permeability -1.669 -1.638 - 1.669 -1.705 -1.652 -2.612 Metabolism CYP2D6 Substrate No No No No No No CYP3A4 Substrate Yes Yes Yes Yes Yes No CYP1A2 Inhibitor No No No No No No CYP2C19 Inhibitor Yes Yes No No No No CYP2C9 Inhibitor No No No No No No CYP2D6 Inhibitor No No No No No No CYP3A4 Inhibitor No No No No No No Excretion Toxicity Total Clearance 0.794 0.808 0.821 0.621 0.611 0.623 Renal oct-2 Substrate No No No No No No AMES Toxicity No No No No No No Hepatotoxicity No No No No No No HeRG 1 Inhibitor No No No No No No Skin Sensitization No No No No No No The figures presented highlight the physicochemical properties of the main phyto-constituents derived from the Argania spinosa spider, represented in the form of radar diagrams. Each graph corresponds to a specific compound, numbered from 1 to 6, and examines six essential parameters that influence their bioavailability: lipophilicity (LIPO), size (SIZE), polarity (POLAR), solubility (INSOLU), flexibility (FLEX), and saturation (INSATU). These characteristics are crucial for assessing the pharmacological potential of these molecules and their capacity to act as therapeutic agents. Here is a detailed analysis of the results for each type of compound. 1. Tocopherols (α-tocopherol, β-tocopherol, γ-tocopherol – 1, 2, 3): The tocopherols are distinguished by high lipophilicity (LIPO), suggesting an excellent ability to traverse lipid cell membranes, which is critical for their absorption. Their moderate size (SIZE) facilitates effective diffusion across biological membranes. Additionally, their molecular flexibility (FLEX) ranges from moderate to high, allowing them to easily interact with biological receptors. However, their low polarity (POLAR) and limited solubility in water (INSOLU) may pose challenges regarding bioavailability in hydrophilic environments. These characteristics are typical of tocopherols, which dissolve in lipid environments, making them optimal for antioxidant functions within cell membranes. 2. Plant Sterols (Spinasterol and Schottenol – 4, 5) : The sterols, represented by spinasterol and schottenol, exhibit a pronounced lipophilicity (LIPO), facilitating their integration into cell membranes and their absorption in lipid biological environments. Their molecular flexibility (FLEX) is moderate, limiting excessive interactions and stabilizing their biological effects. These sterols also show low polarity (POLAR) and restricted aqueous solubility (INSOLU), making them less suited for hydrophilic environments. However, their lipophilic properties render them ideal for applications within cell membranes and for interactions with lipid receptors. 3. Ferulic Acid (6) : Ferulic acid showcases a balanced physicochemical profile. Its lipophilicity (LIPO) is lower than that of tocopherols and sterols, yet still sufficiently high to interact with biological membranes. It possesses relatively high polarity (POLAR), promoting interactions with hydrophilic enzymes and proteins while enhancing its solubility (INSOLU) in aqueous environments. This combination of properties positions it as a versatile candidate for therapeutic applications, particularly as an antioxidant and anti-inflammatory agent. These radar diagrams provide a clear and quick representation of the strengths and weaknesses of each phyto-constituent based on their bioavailability and pharmacological potential. Tocopherols and sterols stand out for their high lipophilicity and compatibility with lipid membranes, although they exhibit limitations due to their low aqueous solubility. In contrast, ferulic acid presents a balanced profile with enhanced solubility and favorable polarity, increasing its applicability in hydrophilic environments. Finally, fatty acids, with their flexibility and lipophilicity, round out this overview by offering optimal membrane bioavailability. The physicochemical properties of the phyto-constituents from Argania spinosa, as visualized in these figures, illustrate their complementarity and relevance for therapeutic applications. Lipophilic compounds, notably tocopherols and sterols, are particularly suited for antioxidant and protective functions within cell membranes, while ferulic acid distinguishes itself through its chemical versatility. These conclusions underscore the potential of the phyto-constituents from Argania spinosa to be leveraged in pharmacological treatments targeting complex mechanisms such as oxidative stress and inflammation. Thus, the SwissADME tool is essential for the in-depth analysis of the pharmacological parameters of these molecules. Molecular docking involves presenting and analyzing results obtained from molecular docking simulations aimed at evaluating the potential of argan oil metabolites as inhibitors of key receptors associated with cell death, triggered by excessive alcohol consumption. These receptors, essential in pathological processes such as oxidative stress, inflammation, and apoptosis, were selected to determine whether the studied metabolites can effectively interact with their active sites. The results are analyzed based on affinity energy scores, which provide insights into the stability of ligand-receptor complexes. A lower binding energy, expressed in kcal/mol, indicates a more stable interaction and, consequently, an enhanced inhibitory potential. Furthermore, specific molecular interactions, such as hydrogen bonds, hydrophobic interactions, and π-π interactions between the ligands and receptor residues, are explored to gain a deeper understanding of the mechanisms that stabilize these complexes. This section also highlights the metabolites demonstrating the best binding affinity, comparing them whenever possible to standard reference molecules. The collected data help identify key interactions that contribute to the stability of the complexes and evaluate the relative effectiveness of each metabolite in inhibiting the targeted receptors. Finally, this analysis is discussed within a biological and pharmacological framework, considering the implications of the results for the potential development of new therapeutic strategies. The conclusions drawn may propose avenues for utilizing argan oil metabolites as protective agents against cellular damage induced by excessive alcohol consumption, thereby paving the way for innovative clinical applications Binding energy : Table 4 binding energy compounds NOX-4 CCR2 PARP F-A -6.4 -4.7 -6.8 Alpha-tochopherol -7.6 -6.7 -8.1 Beta-tochopherol -7 -6.2 -7.6 Gamma-tochopherol -7.3 -6.2 -8 Schottenol -7.9 -6.4 -6.4 Spinasterol -9.3 -7.1 -9.6 ref -8.1 -6.9 -9.2 Molecular docking results reveal a particularly striking and significant finding: among all rigorously examined metabolites, spinasterol stands out distinctly and uniquely as the only molecule exhibiting energy affinity scores that significantly and consistently surpass those of reference molecules for all known targeted receptors, namely NOX4, CCR2, and PARP. The estimated binding energies (-9.3 kcal/mol) for NOX4,( -7.1 kcal/mol) for (CCR2, and − 9.6 kcal/mol) for PARP indicate a remarkable and compelling stability in the interaction of spinasterol with these receptors, thereby strongly suggesting a highly significant inhibitory potential. This strong affinity not only raises the possibility of a critical and transformative role played by spinasterol in modulating signaling pathways that are closely associated with alcohol-induced cell death but also highlights its potential therapeutic relevance. Additionally, another metabolite, schottenol, also displayed noteworthy affinity scores that were impressive, though they were slightly lower than those observed for spinasterol. These compelling and promising findings fully justify their selection for further comprehensive studies that will be centered on their inhibitory potential and therapeutic applications(Bellamma et al., 2023; de Pharmacie et al., 2022; Kristianingsih et al., 2024; Manasa & Suhasin, 2023; Morris et al., 2008; Selsabil Kribaa.; Sharma et al., 2023). Hence, detailed 2D interactions will be illustrated meticulously to visually emphasize their binding characteristics with target receptors, providing clarity and insight into their mechanisms of action. Moreover, both compounds will undergo an in-depth and thorough study through molecular dynamics simulations. This meticulous analysis will evaluate the temporal stability of the formed complexes, deeply explore the conformational fluctuations of the ligands and receptors involved, and identify key and critical molecular interactions that are essential for maintaining these complex formations. Thus, this combined approach of molecular docking, 3D visualization, and molecular dynamics aims to provide an in-depth and comprehensive understanding of the potential of spinasterol and schottenol as significant inhibitors of receptors that are activated by the excessive consumption of alcohol. These results not only open particularly promising avenues for the practical application of these molecules in preventing cellular damage but also provide a solid foundation for future experimental research geared towards therapeutic advancements. Analysis and Discussion of Molecular Interactions of Spinasterol with Target Receptors Molecular docking results highlight significant interactions between spinasterol and the receptors CCR2, NOX4, and PARP, indicating its potential as à notable inhibitor of these targets, which are implicated in alcohol-induced cell death. A detailed examination of these interactions enhances our understanding of the mechanisms governing these affinities while illuminating the various types of molecular interactions that stabilize the formed complexes. Types of observed Interactions : Interactions between spinasterol and the target receptors comprise several essential molecular forces that are crucial for the stability and affinity of the established complexes: 1. Hydrogen Bonds : These interactions play a pivotal role in the molecular recognition process and significantly contribute to the stabilization of protein-ligand complexes. - Despite the predominantly hydrophobic nature of spinasterol, hydrogen bonds have been identified with specific receptor residues, thereby reinforcing the stability of the complexes. 2. Hydrophobic Interactions : Dominating in the complexes formed between spinasterol and its target receptors, these interactions arise from the high lipophilicity of spinasterol. - They promote multiple contacts with amino acids present in the receptors' active sites, optimizing ligand spatial arrangement and stabilizing the complexes. 3. π-π and π-Cation Interactions - While spinasterol is primarily hydrophobic, it can engage with aromatic receptor residues through π-π stacking interactions. - Such interactions have been prominently observed with the tryptophan and phenylalanine residues of PARP and NOX4, playing a crucial role in stabilizing the formed complexes. 4.Van der Waals Forces - Although individually weak, these interactions are numerous and contribute significantly to the overall affinity of spinasterol for its targets, facilitating optimal fitting of the ligand within the binding cavity. Interactions of Spinasterol with Target Receptors 1. Interaction with CCR2 The CCR2 receptor (C-C Motif Chemokine Receptor 2) is critical in regulating the inflammatory response and the recruitment of immune cells. Spinasterol primarily establishes hydrophobic interactions with critical residues at the active site, leading to notable stabilization of the complex. Transient hydrogen bonds were also observed, although their impact is less significant compared to hydrophobic interactions. The considerable affinity of spinasterol suggests a potential for effectively modulating the inflammatory response and associated pathways. 2. Interaction with NOX4 The enzyme NOX4 (NADPH Oxidase 4) is a major source of free radicals, contributing to increased oxidative stress levels and subsequent cell death. Spinasterol interacts primarily with NOX4 through hydrophobic bonding and Van der Waals forces, effectively stabilizing the complex. π-π stacking interactions have also been identified with certain aromatic residues located in the active site, enhancing ligand anchoring and stability. This implies that spinasterol has the potential to inhibit NOX4 activity and reduce excessive oxidative stress production, which is critical for protecting cells from alcohol-related damage. 3. Interaction with PARP (Poly-ADP-ribose) polymerase) plays a significant role in DNA repair and the induction of apoptosis. Excessive activation of PARP can lead to increased NAD + consumption, resulting in severe energy depletion and eventual cell death. Interaction analysis shows that spinasterol forms robust hydrogen and hydrophobic bonds with key residues at the active site. Additionally, π-cation interactions with charged residues further enhance the complex's stability. These results suggest that spinasterol might act as a potential inhibitor of PARP , helping to alleviate cellular damage associated with excessive apoptotic activation and previous stressors. Discussion and Biological Implications The analysis of interactions indicates that spinasterol establishes strong and stable bonds with CCR2, NOX4 , and PARP , positioning it as a potential inhibitor of these receptors. Its significant inhibitory potential relies primarily on hydrophobic interactions, complemented by specific types of interactions (like π-π stacking, Van der Waals forces, and some hydrogen bonds). These findings suggest that spinasterol could concurrently inhibit inflammatory, oxidative, and apoptotic pathways—mechanisms that contribute to alcohol-induced cellular toxicity. However, molecular docking remains a static approach and does not account for dynamic behavior and stability assessments over extended periods. To validate these results and refine our understanding of ligand-receptor interactions, molecular dynamics simulation studies will be pursued. This analysis aims to: - Evaluate the temporal stability of the established complexes. - Measure the conformational fluctuations of spinasterol and the receptors. - Analyze persistent interactions and their significant impacts on ligand stabilization. The findings underscore spinasterol as a promising candidate for specifically inhibiting CCR2 , NOX4 , and PARP receptors due to its persistent and stable interactions. Its significant inhibitory potential, primarily based on hydrophobic interactions and π-π stacking, suggests an effective ability to modulate inflammatory, oxidative, and apoptotic processes induced by alcohol consumption. To confirm these observations, a comprehensive molecular dynamics study will be conducted to assess the stability and persistence of interactions in a more realistic physiological environment, thereby paving the way for potential pharmacological applications. 2D Interactions of Spinasterol 2D interactions are critical for analyzing the bioavailability and toxicity of compounds derived from the spider Arania Spinosa. Utilizing SwissADME, we will evaluate these interactions and determine their potential impact on pharmacology, offering an in-depth understanding of the pharmacological modulation of spinasterol along with its beneficial effects in biological contexts. Molecular Dynamics A thorough examination of molecular dynamics concerning spinasterol's interactions with CCR2, NOX4 , and PARP over a duration of 100 nanoseconds (ns) provides a solid framework for rigorously assessing the stability of the complexes formed between these entities. This comprehensive analysis aims to identify the underlying mechanisms and interactions that directly govern the ligand's affinity for these specific protein targets. These findings are crucial in determining whether spinasterol could effectively serve as an inhibitor influencing significant pathological processes such as inflammation (via CCR2 ), oxidative stress (via NOX4 ), and excessive apoptosis (via PARP). Each of these pathological processes is likely exacerbated by excessive and continuous alcohol consumption, further heightening the urgent need for effective potential treatments. The assessment of Root Mean Square Deviation (RMSD) serves as an essential method for measuring atomic position variations within the complex, demonstrating that all three receptors maintain stable structures throughout the entire 100 ns simulation. Observed fluctuations range notably from 1 to 3 Å, clearly indicating that in the presence of spinasterol, no significant disruptions occur in their initial conformation, thus reinforcing the notion of a stable and enduring interaction within the biological context. Moreover, the RMSD of the ligand itself remains relatively constant throughout the analysis, indicating firmly that spinasterol remains securely anchored within the active site of each receptor, without any notable dissociation recorded during the whole simulation procedure. The rationale supporting the observed stability rests upon a meticulous examination of the Root Mean Square Fluctuation (RMSF), which corroborates prior conclusions by revealing the presence of rigid α-helices that are less prone to flexibility within the three receptors. In contrast, more pronounced fluctuations occur in the extracellular and intracellular loops, which are inherently more flexible and play a dynamic role within the biological functions and signaling capabilities of the proteins. Furthermore, an in-depth analysis of protein-ligand contacts sheds light on a diverse array of crucial interactions necessary for effectively maintaining spinasterol within the active sites of the three studied receptors. Hydrophobic interactions, predominantly prevalent within the complexes, lead to strong bonds with apolar residues located inside the binding cavities, ensuring a durable and robust retention of the ligand along with the interactions established. Additionally, transient hydrogen bonds with certain polar residues further enhance the positioning and optimal anchoring of spinasterol within the complex. Additionally, the identification of π-π stacking and π-cation interactions with aromatic residues contributes substantially to the stabilization of the complex, a phenomenon particularly remarkable with the NOX4 and PARP receptors. Furthermore, water bridges have been detected in each complex, demonstrating that water molecules play a facilitatory role, indirectly contributing to the interaction of spinasterol with the target receptors and indicating a significant stabilization effect under simulated physiological conditions. The analysis of the duration of interactions reveals that several of these contacts are maintained for over 70% of the simulation period, thus attesting to spinasterol's high affinity for the three examined receptors. Notably, the spinasterol-CCR2 interaction is distinguished by prevailing hydrophobic interactions, accompanied by some transient hydrogen bonds, thus ensuring a stable anchor for the ligand without disturbing the initial conformation of the receptor. This strong interaction could potentially lead to meaningful modulation of CCR2 activation, consequently contributing to reducing excessive inflammation, a critical process in alcohol-induced cellular injuries suffered by tissues. Regarding the interaction with NOX4, it is noteworthy that this enzyme, involved significantly in free radical production, demonstrates a strong functional affinity for spinasterol, supported by hydrophobic interactions and π-π stacking, potentially leading to decreased excessive oxidative stress production and protecting cells from damage induced by alcohol in a pathological context. In the case of PARP, this enzyme, which plays a vital role in DNA repair and apoptosis induction, sees its interaction stabilized through hydrophobic interactions, stabilizing hydrogen bonds, and further π-π stacking interactions, suggesting that spinasterol might indeed play a key role in modulating PARP activation and thereby contribute significantly to preventing excessive apoptosis. The evaluation of Ligand RMSF for the three complexes indicates that atomic fluctuations of spinasterol remain low, thereby confirming its impressive conformational stability throughout the simulation. Moreover, the analysis of the ligand's torsion profile highlights that internal rotations of spinasterol are limited, thus ensuring an optimal configuration for its interaction with the three target receptors. To accurately illustrate these results concerning interactions and dynamics, several illustrative figures will be necessary: - The RMSD graph (for the proteins and the ligand) clearly demonstrating the consistent stability of the complex across the simulation. - The RMSF graph (for the proteins) highlighting the observed fluctuations and rigidity in the CCR2, NOX4, and PARP receptors. - The protein-ligand contact graph showing the frequency and nature of the established interactions, visualizing how spinasterol engages with the active sites. - A 3D representation of the complexes displaying hydrogen bonds, hydrophobic interactions, and water bridges within the complexes to visualize the interaction landscapes accurately. - Lastly, the ligand’s torsion profile, aimed at confirming its conformational stability in the context of interactions with the receptors, providing a comprehensive understanding of its structural integrity. In conclusion, the results unequivocally confirm that spinasterol establishes stable and persistent interactions with CCR2, NOX4 , and PARP , indicating a significant inhibitory potential on these targets, all associated with alcohol-induced cellular damage. Its strong affinity relies primarily on hydrophobic and π-π stacking interactions, augmented by hydrogen bonds and water bridges, ensuring a stable anchoring within the active sites of the three receptors. To quantify these observations and precisely assess the binding affinity between spinasterol and each receptor, further energetic analysis employing MM-PBSA/MM-GBSA methods could be pursued to complement this critically important study. These results firmly position spinasterol as a promising candidate for modulating various pathological mechanisms associated with alcoholism, paving the way for more in-depth experimental and pharmacological research in the evolving future. The following figures illustrate comprehensively everything discussed above, enabling a visual understanding of the interactions and dynamics involved. Conclusion This in silico study highlights the potential of Argania spinosa (argan oil) metabolites as inhibitors of key receptors involved in alcohol-induced toxicity, specifically NOX4 (NADPH Oxidase 4), PARP (Poly ADP-ribose Polymerase), and CCR2 (C-C Motif Chemokine Receptor 2). Through a multi-faceted computational approach incorporating ADMET analysis, molecular docking, and molecular dynamics simulations, the study identified spinasterol as the most promising bioactive compound, demonstrating high binding affinity and stability across all three target receptors. These findings suggest that argan oil metabolites could serve as natural therapeutic agents to mitigate oxidative stress, inflammation, and apoptosis associated with excessive alcohol consumption. A key contribution of this study is the detailed characterization of molecular interactions, revealing that hydrophobic interactions, π-π stacking, and hydrogen bonding play crucial roles in receptor inhibition. The results reinforce the potential of natural bioactive compounds in drug discovery and therapeutic intervention against alcohol-induced pathologies. However, further experimental validation through in vitro and in vivo studies is required to confirm these computational findings and elucidate the precise biological mechanisms underlying these interactions. Future Perspectives This research lays the groundwork for several promising avenues of future investigation : 1. Experimental Validation: Future studies should prioritize in vitro assays and in vivo models to confirm the efficacy of spinasterol and other argan oil metabolites in modulating NOX4, PARP, and CCR2 activity under alcohol-induced oxidative stress conditions. 2. Optimization and Drug Development: Structural modifications of spinasterol and related metabolites should be explored to enhance their pharmacokinetic properties, increase bioavailability, and improve target specificity, paving the way for the development of novel natural therapeutic agents. 3. Development of Natural Therapeutics: Given the favorable pharmacological profile of argan oil metabolites, efforts should be directed toward the formulation of nutraceuticals or dietary supplements designed to prevent or alleviate alcohol-related hepatic and neurological damage. 4. Integration into Preventive and Therapeutic Medicine: This study underscores the potential for integrating argan oil metabolites into preventive healthcare strategies for alcohol-induced liver fibrosis, neurodegenerative disorders, and chronic inflammatory conditions, contributing to broader public health initiatives. 5. Exploration of Additional Therapeutic Targets: Beyond alcohol-related toxicity, the antioxidant and anti-inflammatory properties of these bioactive compounds warrant further investigation into their potential applications in metabolic disorders, cardiovascular diseases, and neurodegeneration, thereby expanding their therapeutic scope Overall, this study establishes a scientific foundation for the exploration of Argania spinosa metabolites as potential modulators of oxidative and inflammatory pathways. The insights gained from this work provide a strong rationale for future experimental and translational research, aiming to harness natural bioactive compounds for innovative and sustainable therapeutic interventions. Declarations Author Contribution We, the undersigned, declare that each author has made a substantial contribution to the development of the study entitled:Manuscript Title:In Silico Study of Argan Oil Metabolites: Evaluation of Their Potential to Inhibit Key Receptors Activated by Excessive Alcohol Consumption and Involved in Cell DeathContribution Breakdown:Ayoub Bekkouch: Study design and conception, in silico analyses (molecular docking, ADMET, molecular dynamics), data interpretation, manuscript writing, and revision.Oussama Bekkouch: Contribution to methodology, validation of results, assistance in data analysis, and manuscript drafting.Anas Ziani: Literature review, assistance in writing, and manuscript formatting.Nour E. Bentouhami: Data collection and analysis, assistance in preparing figures and tables.Oumaima Abouyala: Supervision of bioinformatics analyses, critical manuscript review, and validation of employed methodologies.El Arbaoui Marouane: Contribution to result interpretation and technical review.Hamzaoui Abdelghafour: Support in statistical analyses and validation of in silico results.Aboubaker El Hesni: Contribution to discussion and critical analysis of experimental data.Abdelhalem Mesfioui: Scientific supervision, critical manuscript review, and final approval of the submitted version.El Mostafi Hicham: Overall project supervision, methodological coherence oversight, and contribution to clinical and pharmacological aspects.All authors have read and approved the final version of the manuscript and accept full responsibility for the published content.We also confirm that there are no conflicts of interest related to this study and that the presented work is original and has not been published or submitted elsewhere.Issued in Oujda, on 17/02/2025 References Abbassi, A. 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Protection of the brain following cerebral ischemia through the attenuation of PARP-1-induced neurovascular unit damage in rats. Elsevier . Retrieved February 17, 2025, from https://www.sciencedirect.com/science/article/pii/S0006899315005521 Zhang, X., Li, S.-Y., Brown, R. A., & Ren, J. (2004). Ethanol and acetaldehyde in alcoholic cardiomyopathy: from bad to ugly en route to oxidative stress. Alcohol , 32 (3), 175–186. Table 2 Table 2 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6049168","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":417958256,"identity":"b243f146-97f2-4dc5-afbd-4dcb100be438","order_by":0,"name":"Ayoub Bekkouch","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIie3PvWrDMBiF4WMCmhyc0UY0vgWbQCD071YiBJ46ZMxWQ0CTktlZ2rsoHR0E7mLa1aDMnjsmdGkUPDRQtenWQe8kJD18EuBy/dN6QInQP6y8/ArkryQDOcd8JQq/jgkKXtEZtsNIqircP7+xVZx77zs8xTYSNllGC7Qj2hdZtKw1EwS9SEKnuc00d2PqQ7GHwB9TTxwJKKA9G4k7ct+R1+OUjwO5tZGkI1Pal4aUhhAzhdlIWrf8skjadC0rPlkKPhKEiYlMNLeR4Qvf6Nl8G4c13zR7cXPxuFCq2c31tfX7g6l53smW+Xjy3d2uoPzh0OVyuVymT4U2U4uqMyQUAAAAAElFTkSuQmCC","orcid":"","institution":"Faculty of Ibn Tofail University","correspondingAuthor":true,"prefix":"","firstName":"Ayoub","middleName":"","lastName":"Bekkouch","suffix":""},{"id":417958257,"identity":"e7e5c45d-5954-4841-be01-d625e851037a","order_by":1,"name":"Oussama Bekkouch","email":"","orcid":"","institution":"Mohammed First University","correspondingAuthor":false,"prefix":"","firstName":"Oussama","middleName":"","lastName":"Bekkouch","suffix":""},{"id":417958259,"identity":"4a1145c1-2c92-4454-b0c8-172f0f9ba0aa","order_by":2,"name":"Anas Ziani","email":"","orcid":"","institution":"Mohammed First University","correspondingAuthor":false,"prefix":"","firstName":"Anas","middleName":"","lastName":"Ziani","suffix":""},{"id":417958261,"identity":"27cf6d9a-070e-471c-8111-cc958d8eb5c9","order_by":3,"name":"Nour E. Bentouhami","email":"","orcid":"","institution":"Mohammed First University","correspondingAuthor":false,"prefix":"","firstName":"Nour","middleName":"E.","lastName":"Bentouhami","suffix":""},{"id":417958262,"identity":"58ebcc09-714f-4e0d-91af-8d2184a3f700","order_by":4,"name":"Oumaima Abouyaala","email":"","orcid":"","institution":"Faculty of Ibn Tofail University","correspondingAuthor":false,"prefix":"","firstName":"Oumaima","middleName":"","lastName":"Abouyaala","suffix":""},{"id":417958263,"identity":"8ea3b42b-3fdb-48c6-bb6d-f65ce0ceca92","order_by":5,"name":"marouane El arbaoui marouane","email":"","orcid":"","institution":"Faculty of Ibn Tofail University","correspondingAuthor":false,"prefix":"","firstName":"marouane","middleName":"El arbaoui","lastName":"marouane","suffix":""},{"id":417958264,"identity":"8e28e242-ff12-41bb-8fa2-0b65b0f207af","order_by":6,"name":"hicham el mostafi","email":"","orcid":"","institution":"Faculty of Ibn Tofail University","correspondingAuthor":false,"prefix":"","firstName":"hicham","middleName":"el","lastName":"mostafi","suffix":""},{"id":417958265,"identity":"bcd33d9f-e640-4226-a5e5-a91e6958bd91","order_by":7,"name":"abdelghafour Hamzaoui","email":"","orcid":"","institution":"Faculty of Ibn Tofail University","correspondingAuthor":false,"prefix":"","firstName":"abdelghafour","middleName":"","lastName":"Hamzaoui","suffix":""},{"id":417958266,"identity":"9489a10f-d9ec-4da4-adee-6bcecc4965ad","order_by":8,"name":"Aboubaker el Hesni","email":"","orcid":"","institution":"Faculty of Ibn Tofail University","correspondingAuthor":false,"prefix":"","firstName":"Aboubaker","middleName":"el","lastName":"Hesni","suffix":""},{"id":417958267,"identity":"574e4c4c-6c9f-49e9-b0b1-c0e9473938ec","order_by":9,"name":"Abdelhalem Mesfioui","email":"","orcid":"","institution":"Faculty of Ibn Tofail University","correspondingAuthor":false,"prefix":"","firstName":"Abdelhalem","middleName":"","lastName":"Mesfioui","suffix":""}],"badges":[],"createdAt":"2025-02-17 15:08:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6049168/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6049168/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76823380,"identity":"ca322525-2ebe-4ec6-8568-8292e27fe6e8","added_by":"auto","created_at":"2025-02-21 07:10:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1301837,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePARP implication on cell death\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/708daaa84823b1d8de61a602.png"},{"id":76823672,"identity":"221a1455-16e1-4b37-962c-3a323547d94c","added_by":"auto","created_at":"2025-02-21 07:18:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1849840,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNOX-4 and neureun apoptosis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/c48b2b77ae769f698d6b74e9.png"},{"id":76823375,"identity":"0f66508f-ee28-4ce2-ac7e-445b303d9a75","added_by":"auto","created_at":"2025-02-21 07:10:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":696583,"visible":true,"origin":"","legend":"\u003cp\u003ephytoconstituents biovailability radars considering six properties (lipophilicity, size, polarity, solubility, flexibility, and saturation) 1(α-tochopherol, 2 β-tochopherol, 3 γ-tochopherol, 4 spinasterol, 5 schottenol, 6 ferulic acid.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/b924ec42b682274f96f14821.png"},{"id":76823374,"identity":"fb8648a6-0469-4811-8960-95a83d0035ed","added_by":"auto","created_at":"2025-02-21 07:10:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1056741,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003einteractions (1- CCR2/spinasterol ; 2- NOX-4/spinasterol ; 3-PARP /spinasterol)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/411ff98122f41f47eabed827.png"},{"id":76823378,"identity":"74b52070-90e4-44df-bfe2-489bd7949415","added_by":"auto","created_at":"2025-02-21 07:10:46","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1396193,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e« CCR2/spinasterol\u003c/strong\u003e : 1-ligand torsion profile, 2-ligand properties, 3- protein ligand contact, 4-protein RMSF, 5-protein-ligand RMSD, « 6,7,8 » - protein-ligand contacts\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/b645d9fdbfdb376d5b778fbb.png"},{"id":76823388,"identity":"4013f2aa-117f-4b8e-8daa-be079fa5abc6","added_by":"auto","created_at":"2025-02-21 07:10:46","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1503071,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNOX-4/spinasterol\u003c/strong\u003e : 1-ligand torsion profile, 2-ligand properties, 3- protein ligand contact, 4-protein RMSF, 5-protein-ligand RMSD, « 6,7,8 » - protein-ligand contacts\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/cda3b11d1f016acd922ce5a5.png"},{"id":76823381,"identity":"79e93260-1b0d-46a3-940c-dc87dac51694","added_by":"auto","created_at":"2025-02-21 07:10:46","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1227561,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePARP/spinasterol\u003c/strong\u003e : 1-ligand torsion profile, 2-ligand properties, 3- protein ligand contact, 4-protein RMSF, 5-protein-ligand RMSD, « 6,7,8 » - protein-ligand contacts\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/a27753f3c7d051bb296cfba3.png"},{"id":78860594,"identity":"fb212adc-6e6d-4beb-b4ad-6237a0ef371f","added_by":"auto","created_at":"2025-03-20 01:46:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":11398969,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/7eed58f4-862c-4f9b-aa9a-4cbaee7e97c4.pdf"},{"id":76823372,"identity":"1517172e-d0da-4120-9594-f63944a028b3","added_by":"auto","created_at":"2025-02-21 07:10:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":214558,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6049168/v1/944543e0cfe73c04aff1f9c8.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"In Silico Study of Argan Oil Metabolites: Evaluation of Their Potential to Inhibit Key Receptors Activated by Excessive Alcohol Consumption and Involved in Cell Death","fulltext":[{"header":"Introduction","content":"\u003cp\u003eExcessive alcohol consumption has long been recognized as a major and significant cause of liver cell injury\u003cem\u003e(Peacock et al., 2018; World Health Organization, 2018)\u003c/em\u003e. The intricate pathophysiology of alcohol-induced liver disease is known to be quite complex, as it involves numerous biological pathways and mechanisms. The analysis of new therapeutic agents, such as the compounds derived from argan oil along with its various metabolites, is emerging as a promising approach for the discovery and development of new drugs that could potentially aid in mitigating liver damage. A thorough review of the current status of drug modeling studies focused on addressing the impacts of alcohol and its diverse pathophysiologies, however, reveals that many studies conducted thus far are primarily limited to the modeling of ligands. Nevertheless, research efforts concentrating on the identification and characterization of new bioactive molecules derived from argan oil and its metabolites and judging their potential effectiveness to inhibit key receptors that get activated due to excessive alcohol consumption\u003cem\u003e(El Monfalouti et al., 2010; El Mostafi et al., 2020)\u003c/em\u003e, which leads to cellular death, have not yet been thoroughly described in the existing literature. Therefore, this study aimed to systematically screen and rigorously evaluate the potential molecular interactions of twenty previously reported argan oil metabolites against several specific protein receptors known to be involved in alcohol-induced pathophysiological processes. Docking studies were performed using two distinct genome-wide docking approaches, and the resultant score functions were meticulously analyzed to ensure accuracy and reliability. Highly scored putative drug molecules, identified as a result of docking studies, were subsequently subjected to molecular dynamics simulations to assess the structural stability of the resulting complexes over time. The comprehensive screening demonstrated that the biotransformation of argan oil compounds yielded a variety of molecules that exhibited the capability to effectively inhibit key receptors associated with alcohol metabolism.\u003cem\u003e(Huey et al., 2012; Morris et al., 2008)\u003c/em\u003e These promising results may promote the argan oil compound metabolites as potentially valuable components in the prevention or treatment of various alcohol-induced pathologies and liver diseases.\u003c/p\u003e\n\u003ch3\u003e1.1. Background and Rationale\u003c/h3\u003e\n\u003cp\u003eExcessive alcohol consumption, recognized for its detrimental health effects, is a significant contributor to cellular damage, including cell death, which poses substantial medical concerns \u003cem\u003e(GAO et al., 2022)\u003c/em\u003e. This issue extends beyond individual health, representing a critical public health challenge that necessitates focused attention. As Argania spinosa (argan oil) and its bioactive metabolites gain traction in nutrition and health domains \u003cem\u003e(Adlouni, 2010)\u003c/em\u003e, it becomes increasingly vital to explore the potential of these compounds in alleviating the damaging impacts of alcohol on human cells and tissues (Charrouf \u0026amp; Guillaume, 2008; Khong \u0026amp; Chan, 2022) This study primarily aims to bridge the notable research gap concerning this issue through the application of advanced in silico methodologies. Techniques such as molecular docking and molecular dynamics simulations will enable the detailed modeling of intricate interactions between argan oil metabolites and the cell death signaling pathways disrupted by alcohol exposure. By enhancing our understanding of these complex interactions, we aim to better assess the potential protective effects conferred by argan oil metabolites.\u003c/p\u003e \u003cp\u003eAdditionally, this research will provide scientific evidence illustrating how these metabolites may mitigate the cellular damage induced by alcohol. Ultimately, this work aspires to lay a relevant and robust scientific foundation that supports future investigations within a rigorous research framework, paving the path for the development of new preventive and therapeutic strategies against alcohol-induced cellular damage.Historically, argan oil has been celebrated for its balsamic and nourishing properties(Adlouni, 2010; Cherki et al., 2006; El Monfalouti et al., 2010). Within the traditional pharmacopoeia of southwestern Morocco, argan oil has been utilized to address various ailments and is renowned for its ability to promote energy, warmth, and vitality. Despite the extensive identification of various metabolites derived from argan oil, their interactions with key receptors implicated in the pathology of excessive alcohol consumption remain poorly understood. Therefore, the primary goal of this investigation is to examine the interactions of these metabolites with specific receptors associated with these disorders\u003cem\u003e(Bekkouch et al., 2024; Bellamma et al., 2023)\u003c/em\u003e, which are anticipated to influence certain cell death pathways. A comprehensive search for argan oil metabolites was conducted utilizing multiple databases for identification purposes.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.2. Aim and Objectives\u003c/h2\u003e \u003cp\u003eThe ambitions of this research revolve around a comprehensive understanding of the effects of argan oil metabolites, with a particular focus on its richness in molecules. Our main emphasis is on the unsaponifiable fraction, specifically examining those molecules with the highest content in relation to the signaling pathways involved in cell death. This specific focus is justified in the context of alcohol consumption, as we choose enzymes that are directly implicated in this cellular process(Li et al., 2022; Xie et al., 2020). To explore these interactions, we employ advanced in silico methods, such as molecular docking and molecular dynamics. It is also crucial to rigorously assess how these rich metabolites interact with the signaling pathways disrupted by alcohol, while examining the potential consequences of these interactions on human health. Furthermore, our approach aims to identify specific molecular targets that play a fundamental role in these mechanisms, thereby paving the way for novel therapeutic avenues in medicine and pharmacology. By adopting this strategy, we hope to not only enrich existing scientific knowledge but also establish a solid foundation for future applications that could revolutionize prevention and treatment strategies for alcohol-related cellular damage.\u003c/p\u003e \u003c/div\u003e"},{"header":"chemical composition of argan oil","content":"\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eArgan oil composition\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComponent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConcentration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMain Roles\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSource\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnsaturated Fatty Acids\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e~\u0026thinsp;80%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCellular regeneration, reduction of inflammation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco, Cahiers Agricultures\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOleic Acid (Omega-9)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u0026ndash;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCardiovascular health, membrane flexibility.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLinoleic Acid (Omega-6)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u0026ndash;35%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEssential for immune and skin functions.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePolyphenols\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNotable presence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeutralization of ROS, antioxidant properties.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTocopherols (Vitamin E)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e~\u0026thinsp;620 mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProtection of cellular membranes from oxidative damage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCahiers Agricultures\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSterols\u003c/b\u003e (Schottenol, Spinasterol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReduction of inflammation, tissue regeneration.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSqualene\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e~\u0026thinsp;0.3\u0026ndash;0.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePowerful antioxidant, protection against oxidative damage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMinerals\u003c/b\u003e (Potassium, Magnesium)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEnzymatic and electrolyte regulation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVolatile Compounds\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTraces\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eContribution to aroma and sensory quality of the oil.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINRA Morocco\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eArgan oil from Morocco is a natural treasure with a chemical composition that varies based on the extraction method employed. The most common technique involves cold pressing the argan nuts, a traditional method that preserves bioactive compounds while preventing the degradation of fatty acids and antioxidants. This approach ensures the production of a high-quality oil, rich in essential nutrients. Comprehensive analyses of argan oil's chemical composition are conducted using advanced chromatographic techniques. For instance, gas chromatography coupled with mass spectrometry (GC-MS) is employed to identify and quantify fatty acids and sterols. The levels of tocopherols (vitamin E) are frequently measured using high-performance liquid chromatography (HPLC), while spectrophotometric methods quantify polyphenols. Research findings reveal that argan oil is particularly abundant in fatty acids, mainly oleic acid (omega-9) and linoleic acid (omega-6), which collectively account for over 70% of its structure. This high concentration of unsaturated fatty acids imparts moisturizing and nourishing properties to the oil, making it ideal for skin and hair care while also promoting cardiovascular health. Additionally, although present in smaller amounts, palmitic acid (12%) and stearic acid (6%) contribute to the oil's stability and its diverse applications in cosmetics (Abbassi et al., 2014; Adlouni, 2010; Charrouf \u0026amp; Guillaume, 2008; El Monfalouti et al., 2010; Menni et al., 2020). The oil\u0026rsquo;s high tocopherol concentration (ranging from 600 to 900 mg/kg) is a significant asset for its antioxidant properties, playing a crucial role in protecting cells from oxidative stress and slowing skin aging. Moreover, the sterolic fraction, primarily composed of schottenol (46\u0026ndash;49%) and spinasterol (39\u0026ndash;42%), enhances the anti-inflammatory and cholesterol-lowering effects of the oil, justifying its use in the prevention of metabolic disorders. Although polyphenols are present in relatively lower quantities, they bestow anti-inflammatory and antimicrobial properties to the oil while contributing to its oxidative stability. The unsaponifiable fraction, representing between 0.34% and 0.79% of the total composition, includes essential bioactive compounds such as sterols and tocopherols, which reinforce the therapeutic and cosmetic benefits of argan oil (Charrouf \u0026amp; Guillaume, 2010; Hilali et al., 2005; Kharbach et al., 2019).\u003c/p\u003e \u003cp\u003eIn recent years, natural components toxic to humans in high doses and mixtures have been tested in in vivo or in vitro models as promising treatments or protectants against organ injuries caused by various factors. For instance, some phenolic compounds like ellagic acid, curcumin, catechin, and pyrogallol derived from \u0026laquo; A. spinosa \u0026raquo; exhibit hepatoprotective effects due to their anti-inflammatory and pro-antioxidant activities. Most studies have primarily focused on the potential effects and action mechanisms of \u0026laquo; A. spinosa \u0026raquo; and its bioactive compounds when used in isolation. However, given that a multitude of bioactive metabolites from A. spinosa can coexist in tissues, additional research has explored the intricate mechanisms associated with these metabolites.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePotentiel effect on health\u003c/b\u003e :\u003c/p\u003e \u003cp\u003eArgan oil emerges as a particularly rich source of various bioactive compounds, offering numerous health benefits for human well-being. It is notably high in unsaturated fatty acids, including omega-6 and omega-9 fatty acids. These essential fatty acids are vital for our body as they play a crucial role in lowering \"bad\" LDL cholesterol while increasing \"good\" HDL cholesterol. This action aids in enhancing overall cardiovascular health and reducing blood pressure. Furthermore, tocopherols, or vitamin E, present in argan oil, act as powerful antioxidants. These important compounds protect cells from oxidative stress, a harmful process, thus contributing to the prevention of skin aging and providing neuronal protection, emphasizing their significant role in neuroprotection. Additionally, the presence of polyphenols in this precious oil endows it with both anti-inflammatory and antimicrobial properties. These attributes enhance insulin sensitivity and help mitigate the risk of developing type 2 diabetes. Plant sterols, such as schottenol and spinasterol, also play a role by aiding in the reduction of cholesterol absorption in the intestine and may even exhibit potential anticancer effects. Squalene, another remarkable component of argan oil, helps shield the skin from various external aggressors while playing a key role in improving skin hydration and potentially alleviating the appearance of precancerous lesions. Alongside its well-documented anti-aging effects and hepatoprotective properties, argan oil may also significantly reduce neurotoxic effects associated with excessive alcohol consumption. Despite these exceptional qualities, further clinical studies are necessary to validate these findings in humans, as the myriad benefits make argan oil an invaluable ally in the prevention of various chronic diseases (Adlouni, 2010; Berrada et al., 2000; Charrouf \u0026amp; Guillaume, 2008, 2010; Cherki et al., 2006; El Monfalouti et al., 2010)\u003c/p\u003e \u003cp\u003e \u003cb\u003eAlcohol and cell death : PARP, NOX4 et CCR2\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMechanisms of Alcohol Toxicity : The significance of research into molecular pathways as therapeutic targets is underscored by the devastating repercussions of excessive and chronic alcohol consumption. This behavior is a crucial factor in cellular dysfunction and tissue pathologies, particularly in vital organs such as the brain and liver. The toxic effects of alcohol are manifested through complex biological processes that undermine normal tissue function. Central to this toxicity is the metabolism of ethanol, which converts into acetaldehyde, a highly reactive and toxic metabolite (Burton, 2005 ; Nakamura et al., 2003 ; Oba et al., 2008 ; Serio \u0026amp; Gudas, 2020 ; Setshedi et al., 2010 ; Svegliati-Baroni et al., 2001). Acetaldehyde inflicts direct damage on liver cells, resulting in considerable cellular deterioration. Concurrently, alcohol promotes the excessive production of free radicals while depleting antioxidant levels in the liver, thereby heightening oxidative stress and its detrimental effects\u003cem\u003e(Fan et al., 2022; GAO et al., 2022; Yang et al., 2012; X. Zhang et al., 2004)\u003c/em\u003e. Additionally, it triggers a robust inflammatory response, worsening existing injuries and tissue damage. These interconnected mechanisms are pivotal in the pathogenesis of various liver diseases, including fatty liver, fibrosis, and cirrhosis. Three critical molecules, namely PARP (Poly(ADP-ribose) polymerase), NOX4 (NADPH Oxidase 4), and CCR2 (C-C Motif Chemokine Receptor 2), play essential roles in these pathological processes. Their involvement in alcohol-induced cell death intensifies neuronal and hepatic damage\u003cem\u003e(Tang et al., 2022)\u003c/em\u003e. Therefore, it is crucial to investigate these molecular targets in the context of analyzing the effects of argan oil on cell death, especially concerning the alarming issue of excessive alcohol consumption, in order to develop therapeutic strategies aimed at mitigating these harmful health effects.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePARP : Poly(ADP-ribose) Polym\u0026eacute;rase\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePARP\u003c/b\u003e is an enzyme activated in response to \u003cb\u003eDNA\u003c/b\u003e breaks caused by oxidative stress, often amplified by alcohol consumption. A study by Zhou et al. (2003) demonstrated that excessive activation of \u003cb\u003ePARP\u003c/b\u003e can lead to energy depletion and neuronal damage in animal models subjected to oxidative stress. Similarly, Czaja (2015) showed that inhibiting \u003cb\u003ePARP\u003c/b\u003e significantly reduces liver inflammation and cellular damage induced by alcohol. This enzyme repairs \u003cb\u003eDNA\u003c/b\u003e damage by consuming NAD⁺, an essential cofactor for metabolic reactions. However, excessive \u003cb\u003ePARP\u003c/b\u003e activation has deleterious effects\u003cem\u003e(Chen et al.,2016.; Teng et al., 2016)\u003c/em\u003e:\u003c/p\u003e \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eIt depletes NAD⁺ and ATP reserves, leading to a fatal energy deficit for cells.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eIt exacerbates mitochondrial dysfunction, worsening neuronal damage.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eIt promotes inflammation by activating pro-inflammatory mediators. In the liver, PARP contributes to the progression of alcoholic steatohepatitis, while in the brain, its excessive activation is associated with oxidative stress-related neuronal injury. Inhibition of PARP, using compounds like olaparib, has shown protective potential against alcohol-related damage by reducing energy depletion and inflammation. \u003cem\u003e(Li et al., 2022 ; Zhang et al., 2015.)\u003c/em\u003e\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eNOX4 : NADPH Oxidase 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNOX4 is a key enzyme in the production of reactive oxygen species (ROS), playing a central role in alcohol-induced oxidative stress. Studies have shown that the activation of NOX4 in hepatic cells can increase ROS levels by 200%, causing significant damage to lipids and membrane proteins. Furthermore, NOX4 is highly expressed in neurons under chronic alcohol exposure, contributing to neuronal degeneration and amplifying neuroinflammation. This enzyme is expressed in hepatocytes, neurons, and glial cells, where it is highly stimulated by alcohol exposure.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eProduction of \u003cstrong\u003eROS: NOX4\u003c/strong\u003e generates reactive oxygen species \u003cstrong\u003e(ROS)\u003c/strong\u003e that damage lipids, proteins, and \u003cstrong\u003eDNA\u003c/strong\u003e, triggering apoptotic and ferroptotic processes.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eRole in alcohol-induced lesions: o In the liver, \u003cstrong\u003eNOX4\u003c/strong\u003e promotes fibrosis and the progression of alcoholic steatosis. o In the brain, it contributes to neuronal degeneration and neuroinflammation.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eTherapeutic targets: Specific \u003cstrong\u003eNOX4\u003c/strong\u003e inhibitors, such as \u003cstrong\u003eGKT137831\u003c/strong\u003e, have demonstrated significant reductions in oxidative and inflammatory damage in experimental models.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eCCR2\u003c/strong\u003e: C-C Motif Chemokine Receptor 2 \u003cstrong\u003eCCR2\u003c/strong\u003e is a chemokine receptor involved in recruiting immune cells to damaged tissues. This receptor is activated by ligands like \u003cstrong\u003eCCL2\u003c/strong\u003e (also known as \u003cstrong\u003eMCP-1\u003c/strong\u003e), which enhance the attraction of monocytes, macrophages, and T cells to inflammatory sites. Upon activation, \u003cstrong\u003eCCR2\u003c/strong\u003e initiates intracellular signaling cascades involving G-proteins that stimulate pro-inflammatory pathways, including the production of cytokines such as \u003cstrong\u003eTNF-\u0026alpha;\u003c/strong\u003e and \u003cstrong\u003eIL-6.\u003c/strong\u003e Additionally, it modulates the activation of microglial cells in the brain, further amplifying neuroinflammation.(Lowe et al., 2020; Ren et al., 2017; K. Zhang \u0026amp; Luo, 2019) In the liver, \u003cstrong\u003eCCR2\u003c/strong\u003e plays a critical role by promoting the accumulation of pro-inflammatory macrophages and exacerbating liver damage associated with fibrosis and alcoholic steatohepatitis. Under the influence of alcohol, \u003cstrong\u003eCCR2\u003c/strong\u003e expression increases in macrophages, microglia, and endothelial cells, worsening chronic inflammation. We investigate the effects of alcohol on the expression of proteins implicated in these carcinogenic processes across the digestive organs and the liver. A literature review identified several proteins previously considered as drug targets: hydroxy-carboxylic acid receptor (\u0026agrave; G-protein-coupled receptor), metabotropic glutamate receptor, excitatory amino acid transporter, muscarinic acetylcholine receptors, and histone deacetylase. Overactivation of these receptors leads to decreased glucose consumption and reduced lipolysis. Of particular relevance to the central nervous system (\u003cstrong\u003eCNS\u003c/strong\u003e) is the key role of these receptors in facilitating synaptic plasticity and memory formation, where excessive activation can result in excitotoxicity due to increased calcium influx.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eInflammatory Mechanisms\u003c/strong\u003e: - \u003cstrong\u003eCCR2\u003c/strong\u003e promotes the infiltration of monocytes and immune cells into damaged tissues. - It stimulates the release of pro-inflammatory cytokines, such as \u003cstrong\u003eTNF-\u0026alpha;\u003c/strong\u003e and \u003cstrong\u003eIL-6\u003c/strong\u003e, which exacerbate cellular damage. Effects on Alcohol-Related Pathologies: - In the liver, \u003cstrong\u003eCCR2\u003c/strong\u003e plays a pivotal role in the progression of alcoholic steatohepatitis by enhancing inflammation and fibrosis. - In the brain, \u003cstrong\u003eCCR2\u003c/strong\u003e contributes to chronic neuroinflammation, worsening cognitive disorders associated with alcoholism. Potential Therapies: Inhibition of \u003cstrong\u003eCCR2\u003c/strong\u003e (for example, via cenicriviroc) shows promise for reducing inflammatory damage in the context of alcoholism. Interactions Between \u003cstrong\u003ePARP, NOX4\u003c/strong\u003e, and \u003cstrong\u003eCCR2\u003c/strong\u003e: These three molecules act synergistically to establish a vicious cycle that amplifies the toxic effects of alcohol: - \u003cstrong\u003eNOX\u003c/strong\u003e4 generates reactive oxygen species \u003cstrong\u003e(ROS)\u003c/strong\u003e which damage DNA, subsequently activating \u003cstrong\u003ePARP\u003c/strong\u003e. - Excessive activation of \u003cstrong\u003ePARP\u003c/strong\u003e leads to cellular energy depletion, increasing mitochondrial dysfunction and exacerbating cell death. \u003cem\u003e(Zhang et al., 2018)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e-Concurrently, \u003cstrong\u003eCCR2\u003c/strong\u003e intensifies the infiltration of immune cells and the release of cytokines, worsening inflammation and oxidative damage. This interconnection renders these molecules particularly attractive as combined therapeutic targets for interrupting the pathological process. Therapeutic Strategies:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1. PARP\u003c/strong\u003e Inhibitors: Aim to reduce energy depletion and prevent neuronal and hepatic damage. (Chen et al., n.d.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. NOX4\u003c/strong\u003e Inhibitors: Seek to limit \u003cstrong\u003eROS\u003c/strong\u003e production and alleviate oxidative stress. (Xie et al., 2020)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. CCR2\u003c/strong\u003e Inhibitors: Focus on blocking the infiltration of inflammatory cells and reducing chronic inflammation. (K. Zhang et al., 2018)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u003c/strong\u003e Combined Approaches: An integrated therapy targeting \u003cstrong\u003ePARP, NOX4\u003c/strong\u003e, and \u003cstrong\u003eCCR2\u003c/strong\u003e could provide synergistic protection against alcohol-induced damage.\u003c/p\u003e\n\u003cp\u003eAlcohol induces cell death through complex mechanisms involving \u003cstrong\u003ePARP, NOX4\u003c/strong\u003e, and \u003cstrong\u003eCCR2\u003c/strong\u003e, which work together to amplify oxidative stress, inflammation, and energy dysfunction. These interactions extend beyond mere cellular toxicity, paving the way for innovative therapeutic strategies. Inhibitors targeting these molecules have the potential to disrupt the pathological cascades responsible for tissue damage. Future research may prioritize clinical trials combining these inhibitors with other innovative approaches, assessing their effectiveness in mitigating neurodegenerative and hepatic complications. A more profound understanding of molecular interaction networks in these contexts could revolutionize the management of patients affected by alcoholism. Insights into these interactions offer promising prospects for developing targeted and combined therapies capable of preventing or alleviating alcohol-induced tissue injuries. Such strategies could transform the management of complications associated with alcohol use and enhance the quality of life for affected individuals. Additionally, CCR2 is crucial for understanding ethanol-induced excitotoxicity, serving as a primary transporter of excitatory amino acids in the brain and working alongside various other proteins to facilitate glutamate transport and prevent toxic overstimulation of neurotransmitter pathways. Alcohol disrupts this function, potentially worsening receptor interactions associated with the adverse neurobehavioral effects of fetal alcohol exposure. In the case of muscarinic receptors, excessive activation can lead to central nervous system suppression. Furthermore, the enzyme responsible for deacetylating histones surrounding oncogenes with carcinogenic properties is significantly inhibited, resulting in hyperacetylation and diminished gene expression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe Importance of Research on Molecular Pathways as Therapeutic Targets\u003c/strong\u003e :\u003c/p\u003e\n\u003cp\u003eInvestigations into molecular pathways such as PARP, NOX4, and CCR2 as therapeutic targets are gaining increasing attention in the biomedical field, given their roles in complex pathological processes. These molecules are central to the pathophysiological mechanisms associated with cell death, significantly manifested through the amplification of oxidative stress, chronic inflammation, and mitochondrial dysfunction. A targeted approach toward these pathways could facilitate the development of innovative therapeutic strategies, particularly aimed at preventing or alleviating cellular damage caused by complex pathologies, such as those often linked to excessive alcohol consumption and its detrimental effects on the body. Therapeutic Potential of Argan Oil Metabolites, widely recognized for its exceptional richness in bioactive compounds such as polyphenols, tocopherols, and unsaturated fatty acids, represents a natural resource of notable interest for its unique protective properties against alcohol-induced damage\u003cem\u003e(Bekkouch et al., 2025)\u003c/em\u003e. These metabolites are distinguished by their well-established antioxidant and anti-inflammatory characteristics across various contexts, which could be leveraged to modulate the activities of PARP, NOX4, and CCR2 in a targeted manner. While the effectiveness of these compounds in inhibiting these molecular targets still requires thorough exploration in specific preclinical models, their potential truly opens up promising avenues for the development of novel naturally-derived therapeutic approaches, there by providing viable solutions to complex disorders.\u003c/p\u003e"},{"header":"In Silico Methodology in Biology (ADME, AutoDock, Schrödinger)","content":"\u003ch3\u003e1. SwissADME :\u003c/h3\u003e\n\u003cp\u003eIs an innovative online tool developed by the Swiss Institute of Bioinformatics (SIB) to predict a variety of pharmacological and pharmacokinetic properties relevant to bioactive molecules. Fully free of charge and easily accessible, it has rapidly gained recognition as a preferred resource in the fields of medicinal chemistry and pharmacology for evaluating the essential characteristics related to absorption, distribution, metabolism, excretion (ADME), and potential toxicity (ADMET) of diverse chemical compounds. By simply inputting a molecular structur either in SMILES format or by utilizing a convenient drawing interface—SwissADME generates precise and comprehensive analyses of several crucial parameters. This powerful tool facilitates a thorough evaluation of absorption characteristics, including essential metrics like water solubility and intestinal permeability—two critical elements needed to predict the efficacy and functionality of molecules when administered via oral routes. Additionally, it supplies vital data regarding pharmacokinetic properties, such as the ability of various molecules to cross the blood-brain barrier (BBB) and their potential role as substrates for P-glycoprotein (P-gp), both significantly influencing their overall bioavailability and effectiveness. SwissADME features detailed \"drug-likeness\" analyses based on well-established rules of Lipinski, Ghose, Veber, and other established criteria, enabling researchers to conduct compliance assessments of a molecule with industry-standard drug characteristics. Moreover, the tool identifies potential interactions with cytochrome P450 enzymes, which are critically important for understanding the complex metabolic pathways of various molecules and effectively predicting possible drug-drug interactions that may arise within biological systems. While SwissADME does not provide a comprehensive toxicological evaluation, it allows users to detect alerts based on the physicochemical properties of the examined molecules. By seamlessly combining sophisticated predictive models with rigorous and precise calculations, SwissADME proves to be an indispensable instrument for the initial stages of drug design and discovery. Its advanced capacity to reduce costs and significantly shorten the timelines often associated with the development of therapeutic molecules renders it an invaluable resource for optimizing therapeutic candidates and accelerating research advancements in the complex field of pharmacology. \u003cem\u003e(Bekkouch et al., 2025; Zekri et al., n.d.)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Docking\u003c/strong\u003e : The utilization of AutoDock Vina for ligand-receptor docking simulations is structured around a methodical approach encompassing several essential and interrelated steps. Initially, it is crucial to diligently download and install the necessary software, including both AutoDock Vina and AutoDockTools (ADT), carefully adhering to the comprehensive guidelines outlined on the official website. The structure preparation phase begins with the importing of the target macromolecule, which is often sourced from the reputable Protein Data Bank (PDB), alongside the ligands of interest for the docking studies. Within ADT, the macromolecule structure is meticulously cleaned by removing extraneous water molecules, adding polar hydrogens, and assigning Gasteiger partial charges, before saving it in the specialized PDBQT format tailored for AutoDock use. Each ligand is similarly imported and subjected to rigorous processing, encompassing the addition of hydrogens and proper assignment of partial charges. Rotatable bonds within each ligand are identified thoughtfully to determine the root atom around which flexibility is permitted during the docking process, after which every ligand is saved in the required PDBQT format, ensuring compatibility with the docking software. Next, the docking box is configured adequately to define the spatial area of potential interaction between the ligands and the receptor. This necessitates the careful specification of dimensions and positional coordinates of the grid, supplemented by the number of points allocated in each spatial direction and the associated spacing between them, typically set at 0.375 Å for optimal resolution. A docking parameter file (DPF) is subsequently generated to establish the various search algorithm parameters. These may include a hybrid genetic algorithm coupled with a local search (GA-LS) approach to yield enhanced accuracy for the docking results. Parameters outlined within the DPF encompass the maximum permissible number of energy evaluations alongside the required search cycles. Once the DPF file is finalized and carefully reviewed, the energy map undergoes calculation through the AutoGrid utility, followed by the docking process itself using the AutoDock Vina software, executed via terminal commands. Results of the docking are meticulously analyzed from the generated log file, wherein the binding affinity scores of the ligand-receptor complexes are examined in detail. These docking results are subsequently visualized in 3D using ADT, where various conformations are clustered systematically according to their respective binding energy, with the lowest scores indicating the best affinity outcomes. A comprehensive final evaluation is conducted to validate the convergence of the simulations utilizing various clustering methods and to strategically select the conformation that exhibits the best stability alongside the most relevant interactions with the receptor's active site. \u003cem\u003e(Huey et al., 2012; Morris et al., 2008)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Molecular Dynamics\u003c/strong\u003e : In this detailed study, molecular dynamics methodology was rigorously employed to refine the outcomes of the docking results obtained previously. The software used specifically for these intricate simulations is Schrödinger. Molecular structures were diligently prepared with the help of the Protein Preparation Wizard tool, which allows for the precise adjustment of protonation states, the addition of missing ions, correction of hydrogen bonds, and thorough structural optimizations that are critical for obtaining accurate simulations. Ligands were processed via the LigPrep module, ensuring the selection of optimal conformations that would contribute to the reliability of the overall study. Molecular dynamics simulations were systematically conducted using the powerful Desmond simulation engine, over extensive periods of 100 nanoseconds within an explicitly solvated environment utilizing the TIP3P solvent model, carefully maintaining isotonic conditions within an NPT ensemble (constant pressure and temperature) throughout the simulation procedure. The temperature was stabilized meticulously at 300 K and the pressure at 1 atm using the Nose-Hoover thermostat algorithm and the Martyna-Tobias-Klein barostat techniques, which are essential for maintaining the integrity of the molecular environment. Protein-ligand interactions were thoroughly explored using the advanced Simulation Interaction Diagram tool, which allowed for in-depth analysis of the evolution of hydrogen bonds, hydrophobic interactions, and binding energies over the course of the simulation timeline. The analysis of results gleaned from these molecular dynamics simulations revealed the stability of the formed complexes by examining RMSD (Root Mean Square Deviation) fluctuations and the consistency of critical interactions throughout the total simulated period, providing valuable insights into the dynamics of the ligand-receptor binding process. \u003cem\u003e(Bai et al., 2023; Bekkouch et al., 2024; Hadi et al., 2023; Huey et al., 2012; Morris et al., 2008)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelection of Bioactive Compounds from Argan Oil\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe meticulous selection of bioactive molecules found within the renowned argan oil, such as tocopherols, spinasterol, schottenol, and ferulic acid, is predicated not only on their notable concentrations within this valuable and highly sought-after oil but also on their remarkable synergistic properties that complement one another in a harmonious manner (Charrouf \u0026amp; Guillaume, 2008; El Abbassi et al., 2014; Kharbach et al., 2019). Furthermore, these compounds exhibit the capacity to directly target fundamental pathological mechanisms that are associated with the significant damages inflicted by alcohol consumption. Tocopherols, which are notably abundant in argan oil, serve as potent antioxidants with the critical ability to safeguard cell membranes from the harmful effects of lipid oxidation, which is often induced by the presence of free radicals. This protective mechanism proves to be crucial in addressing the cellular toxicity linked to alcohol exposure. In addition, spinasterol and schottenol, whose concentrations in argan oil are also quite significant, exhibit valuable anti-inflammatory properties by effectively modulating the secretion of pro-inflammatory cytokines while supporting essential cellular regeneration. This functionality is particularly important for alleviating injuries that can adversely affect not just the liver but also the nervous system. Ferulic acid, another major polyphenol that is found in abundance within argan oil, plays a pivotal role in negating reactive oxygen species (ROS)(Charrouf \u0026amp; Guillaume, 2008; Drissi et al., 2004; Gharby et al., 2011; Khong \u0026amp; Chan, 2022). This action effectively assists in preventing oxidative damage to vital cellular components such as DNA, proteins, and lipids. The exceptional richness of argan oil in these diverse bioactive components significantly enhances their relevance as a strategic selection for the current study, which aims to further delve into their potential effects. By collectively addressing oxidative stress, chronic inflammation, and mitochondrial dysfunctions that can arise, these bioactive molecules offer a comprehensive and integrated approach toward mitigating the negative consequences of excessive alcohol consumption on human health. This judicious selection of bioactive candidates is thus firmly substantiated by their well-documented efficacy in a variety of experimental models that focus on oxidative stress and inflammation. In addition, their remarkably high concentrations in argan oil position these compounds as particularly promising candidates for the development of innovative natural therapeutic applications. Such applications could provide genuine solutions to the pressing public health challenges posed by alcohol-related damage, thereby enhancing the overall well-being of individuals affected by excessive alcohol consumption and its associated complications.\u003c/p\u003e\n\n\n\n\n\n\n\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\n\u003cp\u003e\u003c/p\u003e\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n"},{"header":"Résults and discussion","content":"\u003cp\u003e\u003cstrong\u003eIn Silico Analysis of ADMET Properties of Argania spinosa Metabolites: Potential for Drug Developmen\u003c/strong\u003e :\u003c/p\u003e\u003cp\u003eThe efficacy of a drug is largely determined by its absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, which can greatly limit its clinical application and overall therapeutic effectiveness\u003cem\u003e(Daina et al., 2017)\u003c/em\u003e. Pharmacokinetics presents a major challenge in the development of new drugs, particularly due to the high costs associated with experimental testing and lengthy timelines required for such investigations. In this context, our comprehensive study employs advanced in silico approaches to meticulously evaluate the ADMET properties and assess the therapeutic potential of Argania spinosa metabolites as promising candidates for future drug development. Our detailed analysis encompasses various critical parameters, including in-depth evaluation of physicochemical characteristics, absorption profiles, distribution capabilities, metabolism pathways, excretion rates, and potential adverse effects, all systematically applied to compounds numbered from 1 to 8 as listed in Table\u0026nbsp;2. To ensure full compliance with established pharmaceutical standards, which are crucial for any potential drug entity, Lipinski’s Rule of Five was meticulously utilized during our assessment. This foundational rule specifies essential criteria, such as having fewer than 5 hydrogen bond donors, fewer than 10 hydrogen bond acceptors, a molecular weight (MW) of less than 500 Da, and a logP (MLOGP) not exceeding 4.15. Notably, every single analyzed phytoconstituent meets these fundamental criteria, indicating their promising oral bioavailability, which is further supported by an impressive average score of 0.55. Furthermore, concerning solubility, the compounds exhibit satisfactory aqueous solubility with logS values ranging between − 4 and 0, reflecting their considerable ability to dissolve effectively in a physiological environment conducive to human use. The absorption results reveal a compelling narrative, as all compounds exhibit high permeability across Caco-2 cells, indicating a strong intestinal absorption capacity in humans, which is essential for any potential oral drug. No substrate activity for P-glycoprotein was observed among the tested compounds; however, it is noteworthy that all compounds, with the sole exception of α-tocopherol, displayed inhibition of P-glycoproteins P1 and P2. Concerning distribution, the apparent volume of distribution (VDss) values suggest very good plasma distribution characteristics for the compounds evaluated. Both α and β-tocopherols appear particularly well-suited to effectively crossing the blood-brain barrier, endowing them with significant therapeutic potential in various neuroprotective strategies that merit further investigation. The metabolism analysis, conducted with precision, indicated no significant interactions with critical cytochrome P450 enzymes, including the isoenzymes CYP2D6, CYP1A2, CYP2C9, and CYP3A4, both when evaluated as substrates and inhibitors. This lack of interaction with major metabolic pathways underscores the safety profile and pharmacokinetic compatibility of these metabolites as potential therapeutic agents. Overall, the findings of this study point towards the promising future of Argania spinosa metabolites in drug development, effectively highlighting their significant therapeutic benefits alongside favorable pharmacokinetic properties.\u003c/p\u003e\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMET profile1(α-tochopherol, 2 β-tochopherol, 3 γ-tochopherol, 4 spinasterol; 5-schottenol, 6 ferulic acid\u003c/strong\u003e, \u003cem\u003e(Bekkouch et al., 2024)\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eCompounds\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" rowspan=\"10\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug- likeness\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eLipinski’s rule of five\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eBioavailability Score\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eWater\u003c/p\u003e\n \u003cp\u003eSolubility\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-6.901\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-7.417\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e7.602\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-6.773\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-6.682\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.817\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCaco2\u003c/p\u003e\n \u003cp\u003ePermeability\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e1.345\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e1.73\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e1.458\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e1.201\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e1.213\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eIntestinal\u003c/p\u003e\n \u003cp\u003eAbsorption\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e89.782\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e89.452\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e90.43\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e94.464\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e94.97\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e93.685\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eSkin Permeability\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.683\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.709\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.62\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.783\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.783\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.72\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eP-glycoprotein\u003c/p\u003e\n \u003cp\u003eSubstrate\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eP-glycoprotein- 1 Inhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eP-glycoprotein- 2 Inhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eVDss (human)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.709\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.946\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.732\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.178\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.367\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eDistribution\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eBBB\u003c/p\u003e\n \u003cp\u003ePermeability\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.876\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.915\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.739\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.781\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.771\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.239\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCNS\u003c/p\u003e\n \u003cp\u003ePermeability\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.669\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.638\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e1.669\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.705\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.652\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.612\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" rowspan=\"7\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetabolism\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCYP2D6\u003c/p\u003e\n \u003cp\u003eSubstrate\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCYP3A4\u003c/p\u003e\n \u003cp\u003eSubstrate\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCYP1A2\u003c/p\u003e\n \u003cp\u003eInhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCYP2C19\u003c/p\u003e\n \u003cp\u003eInhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCYP2C9\u003c/p\u003e\n \u003cp\u003eInhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCYP2D6\u003c/p\u003e\n \u003cp\u003eInhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCYP3A4\u003c/p\u003e\n \u003cp\u003eInhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eExcretion\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eToxicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Clearance\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.794\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.808\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.821\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.621\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.611\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0.623\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal oct-2 Substrate\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eAMES Toxicity\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eHepatotoxicity\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eHeRG 1\u003c/p\u003e\n \u003cp\u003eInhibitor\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSkin\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSensitization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003cp\u003eThe figures presented highlight the physicochemical properties of the main phyto-constituents derived from the Argania spinosa spider, represented in the form of radar diagrams. Each graph corresponds to a specific compound, numbered from 1 to 6, and examines six essential parameters that influence their bioavailability: lipophilicity (LIPO), size (SIZE), polarity (POLAR), solubility (INSOLU), flexibility (FLEX), and saturation (INSATU). These characteristics are crucial for assessing the pharmacological potential of these molecules and their capacity to act as therapeutic agents. Here is a detailed analysis of the results for each type of compound.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e1. Tocopherols\u003c/strong\u003e (α-tocopherol, β-tocopherol, γ-tocopherol – 1, 2, 3): The tocopherols are distinguished by high lipophilicity (LIPO), suggesting an excellent ability to traverse lipid cell membranes, which is critical for their absorption. Their moderate size (SIZE) facilitates effective diffusion across biological membranes. Additionally, their molecular flexibility (FLEX) ranges from moderate to high, allowing them to easily interact with biological receptors. However, their low polarity (POLAR) and limited solubility in water (INSOLU) may pose challenges regarding bioavailability in hydrophilic environments. These characteristics are typical of tocopherols, which dissolve in lipid environments, making them optimal for antioxidant functions within cell membranes.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e2. Plant Sterols (Spinasterol and Schottenol – 4, 5)\u003c/strong\u003e: The sterols, represented by spinasterol and schottenol, exhibit a pronounced lipophilicity (LIPO), facilitating their integration into cell membranes and their absorption in lipid biological environments. Their molecular flexibility (FLEX) is moderate, limiting excessive interactions and stabilizing their biological effects. These sterols also show low polarity (POLAR) and restricted aqueous solubility (INSOLU), making them less suited for hydrophilic environments. However, their lipophilic properties render them ideal for applications within cell membranes and for interactions with lipid receptors.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e3. Ferulic Acid (6)\u003c/strong\u003e: Ferulic acid showcases a balanced physicochemical profile. Its lipophilicity (LIPO) is lower than that of tocopherols and sterols, yet still sufficiently high to interact with biological membranes. It possesses relatively high polarity (POLAR), promoting interactions with hydrophilic enzymes and proteins while enhancing its solubility (INSOLU) in aqueous environments. This combination of properties positions it as a versatile candidate for therapeutic applications, particularly as an antioxidant and anti-inflammatory agent.\u003c/p\u003e\u003cp\u003eThese radar diagrams provide a clear and quick representation of the strengths and weaknesses of each phyto-constituent based on their bioavailability and pharmacological potential. Tocopherols and sterols stand out for their high lipophilicity and compatibility with lipid membranes, although they exhibit limitations due to their low aqueous solubility. In contrast, ferulic acid presents a balanced profile with enhanced solubility and favorable polarity, increasing its applicability in hydrophilic environments. Finally, fatty acids, with their flexibility and lipophilicity, round out this overview by offering optimal membrane bioavailability. The physicochemical properties of the phyto-constituents from Argania spinosa, as visualized in these figures, illustrate their complementarity and relevance for therapeutic applications. Lipophilic compounds, notably tocopherols and sterols, are particularly suited for antioxidant and protective functions within cell membranes, while ferulic acid distinguishes itself through its chemical versatility. These conclusions underscore the potential of the phyto-constituents from Argania spinosa to be leveraged in pharmacological treatments targeting complex mechanisms such as oxidative stress and inflammation. Thus, the SwissADME tool is essential for the in-depth analysis of the pharmacological parameters of these molecules.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMolecular docking\u003c/strong\u003e\u003c/p\u003e\u003cp\u003einvolves presenting and analyzing results obtained from molecular docking simulations aimed at evaluating the potential of argan oil metabolites as inhibitors of key receptors associated with cell death, triggered by excessive alcohol consumption. These receptors, essential in pathological processes such as oxidative stress, inflammation, and apoptosis, were selected to determine whether the studied metabolites can effectively interact with their active sites. The results are analyzed based on affinity energy scores, which provide insights into the stability of ligand-receptor complexes. A lower binding energy, expressed in kcal/mol, indicates a more stable interaction and, consequently, an enhanced inhibitory potential. Furthermore, specific molecular interactions, such as hydrogen bonds, hydrophobic interactions, and π-π interactions between the ligands and receptor residues, are explored to gain a deeper understanding of the mechanisms that stabilize these complexes. This section also highlights the metabolites demonstrating the best binding affinity, comparing them whenever possible to standard reference molecules. The collected data help identify key interactions that contribute to the stability of the complexes and evaluate the relative effectiveness of each metabolite in inhibiting the targeted receptors. Finally, this analysis is discussed within a biological and pharmacological framework, considering the implications of the results for the potential development of new therapeutic strategies. The conclusions drawn may propose avenues for utilizing argan oil metabolites as protective agents against cellular damage induced by excessive alcohol consumption, thereby paving the way for innovative clinical applications\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eBinding energy\u003c/strong\u003e:\u003c/p\u003e\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ebinding energy\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003ecompounds\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eNOX-4\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eCCR2\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003ePARP\u003c/p\u003e\n \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eF-A\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-6.4\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.7\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-6.8\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eAlpha-tochopherol\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-7.6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e-6.7\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-8.1\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eBeta-tochopherol\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-7\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e-6.2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-7.6\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eGamma-tochopherol\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-7.3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e-6.2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-8\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eSchottenol\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-7.9\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e-6.4\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-6.4\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eSpinasterol\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-9.3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e-7.1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-9.6\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eref\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-8.1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e-6.9\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e-9.2\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003cp\u003eMolecular docking results reveal a particularly striking and significant finding: among all rigorously examined metabolites, spinasterol stands out distinctly and uniquely as the only molecule exhibiting energy affinity scores that significantly and consistently surpass those of reference molecules for all known targeted receptors, namely NOX4, CCR2, and PARP. The estimated binding energies (-9.3 kcal/mol) for NOX4,( -7.1 kcal/mol) for (CCR2, and − 9.6 kcal/mol) for PARP indicate a remarkable and compelling stability in the interaction of spinasterol with these receptors, thereby strongly suggesting a highly significant inhibitory potential. This strong affinity not only raises the possibility of a critical and transformative role played by spinasterol in modulating signaling pathways that are closely associated with alcohol-induced cell death but also highlights its potential therapeutic relevance. Additionally, another metabolite, schottenol, also displayed noteworthy affinity scores that were impressive, though they were slightly lower than those observed for spinasterol. These compelling and promising findings fully justify their selection for further comprehensive studies that will be centered on their inhibitory potential and therapeutic applications(Bellamma et al., 2023; de Pharmacie et al., 2022; Kristianingsih et al., 2024; Manasa \u0026amp; Suhasin, 2023; Morris et al., 2008; Selsabil Kribaa.; Sharma et al., 2023). Hence, detailed 2D interactions will be illustrated meticulously to visually emphasize their binding characteristics with target receptors, providing clarity and insight into their mechanisms of action. Moreover, both compounds will undergo an in-depth and thorough study through molecular dynamics simulations. This meticulous analysis will evaluate the temporal stability of the formed complexes, deeply explore the conformational fluctuations of the ligands and receptors involved, and identify key and critical molecular interactions that are essential for maintaining these complex formations. Thus, this combined approach of molecular docking, 3D visualization, and molecular dynamics aims to provide an in-depth and comprehensive understanding of the potential of spinasterol and schottenol as significant inhibitors of receptors that are activated by the excessive consumption of alcohol. These results not only open particularly promising avenues for the practical application of these molecules in preventing cellular damage but also provide a solid foundation for future experimental research geared towards therapeutic advancements.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAnalysis and Discussion of Molecular Interactions of Spinasterol with Target Receptors\u0026nbsp;\u003c/strong\u003eMolecular docking results highlight significant interactions between spinasterol and the receptors CCR2, NOX4, and PARP, indicating its potential as à notable inhibitor of these targets, which are implicated in alcohol-induced cell death. A detailed examination of these interactions enhances our understanding of the mechanisms governing these affinities while illuminating the various types of molecular interactions that stabilize the formed complexes.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTypes of observed Interactions\u003c/strong\u003e :\u003c/p\u003e\u003cp\u003eInteractions between spinasterol and the target receptors comprise several essential molecular forces that are crucial for the stability and affinity of the established complexes:\u003c/p\u003e\u003cp\u003e\u003cspan\u003e\u003cstrong\u003e1. Hydrogen Bonds\u003c/strong\u003e : These interactions play a pivotal role in the molecular recognition process and significantly contribute to the stabilization of protein-ligand complexes. - Despite the predominantly hydrophobic nature of spinasterol, hydrogen bonds have been identified with specific receptor residues, thereby reinforcing the stability of the complexes.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e\u003cstrong\u003e2. Hydrophobic Interactions\u003c/strong\u003e : Dominating in the complexes formed between spinasterol and its target receptors, these interactions arise from the high lipophilicity of spinasterol. - They promote multiple contacts with amino acids present in the receptors' active sites, optimizing ligand spatial arrangement and stabilizing the complexes.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e\u003cstrong\u003e3. π-π and π-Cation Interactions\u003c/strong\u003e - While spinasterol is primarily hydrophobic, it can engage with aromatic receptor residues through π-π stacking interactions. - Such interactions have been prominently observed with the tryptophan and phenylalanine residues of PARP and NOX4, playing a crucial role in stabilizing the formed complexes.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e\u003cstrong\u003e4.Van der Waals Forces\u003c/strong\u003e\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e- Although individually weak, these interactions are numerous and contribute significantly to the overall affinity of spinasterol for its targets, facilitating optimal fitting of the ligand within the binding cavity.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eInteractions of Spinasterol with Target Receptors\u003c/strong\u003e\u003c/p\u003e\u003ch3\u003e1. Interaction with CCR2\u003c/h3\u003e\u003cp\u003eThe CCR2 receptor (C-C Motif Chemokine Receptor 2) is critical in regulating the inflammatory response and the recruitment of immune cells. Spinasterol primarily establishes hydrophobic interactions with critical residues at the active site, leading to notable stabilization of the complex. Transient hydrogen bonds were also observed, although their impact is less significant compared to hydrophobic interactions. The considerable affinity of spinasterol suggests a potential for effectively modulating the inflammatory response and associated pathways.\u003c/p\u003e\u003cp\u003e\u003cspan\u003e\u003cstrong\u003e2. Interaction with NOX4 The enzyme NOX4 (NADPH Oxidase 4)\u003c/strong\u003e is a major source of free radicals, contributing to increased oxidative stress levels and subsequent cell death. Spinasterol interacts primarily with \u003cstrong\u003eNOX4\u003c/strong\u003e through hydrophobic bonding and Van der Waals forces, effectively stabilizing the complex. π-π stacking interactions have also been identified with certain aromatic residues located in the active site, enhancing ligand anchoring and stability. This implies that spinasterol has the potential to inhibit\u0026nbsp;\u003cstrong\u003eNOX4\u003c/strong\u003e activity and reduce excessive oxidative stress production, which is critical for protecting cells from alcohol-related damage.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e\u003cstrong\u003e3. Interaction with PARP (Poly-ADP-ribose) polymerase)\u003c/strong\u003e plays a significant role in \u003cstrong\u003eDNA\u003c/strong\u003e repair and the induction of apoptosis. Excessive activation of \u003cstrong\u003ePARP\u003c/strong\u003e can lead to increased \u003cstrong\u003eNAD +\u003c/strong\u003e consumption, resulting in severe energy depletion and eventual cell death. Interaction analysis shows that spinasterol forms robust hydrogen and hydrophobic bonds with key residues at the active site. Additionally, π-cation interactions with charged residues further enhance the complex's stability. These results suggest that spinasterol might act as a potential inhibitor of \u003cstrong\u003ePARP\u003c/strong\u003e, helping to alleviate cellular damage associated with excessive apoptotic activation and previous stressors. Discussion and Biological Implications The analysis of interactions indicates that spinasterol establishes strong and stable bonds with \u003cstrong\u003eCCR2, NOX4\u003c/strong\u003e, and \u003cstrong\u003ePARP\u003c/strong\u003e, positioning it as a potential inhibitor of these receptors. Its significant inhibitory potential relies primarily on hydrophobic interactions, complemented by specific types of interactions (like π-π stacking, Van der Waals forces, and some hydrogen bonds). These findings suggest that spinasterol could concurrently inhibit inflammatory, oxidative, and apoptotic pathways—mechanisms that contribute to alcohol-induced cellular toxicity. However, molecular docking remains a static approach and does not account for dynamic behavior and stability assessments over extended periods. To validate these results and refine our understanding of ligand-receptor interactions, molecular dynamics simulation studies will be pursued. This analysis aims to: - Evaluate the temporal stability of the established complexes. - Measure the conformational fluctuations of spinasterol and the receptors. - Analyze persistent interactions and their significant impacts on ligand stabilization. The findings underscore spinasterol as a promising candidate for specifically inhibiting \u003cstrong\u003eCCR2\u003c/strong\u003e, \u003cstrong\u003eNOX4\u003c/strong\u003e, and \u003cstrong\u003ePARP\u003c/strong\u003e receptors due to its persistent and stable interactions. Its significant inhibitory potential, primarily based on hydrophobic interactions and π-π stacking, suggests an effective ability to modulate inflammatory, oxidative, and apoptotic processes induced by alcohol consumption. To confirm these observations, a comprehensive molecular dynamics study will be conducted to assess the stability and persistence of interactions in a more realistic physiological environment, thereby paving the way for potential pharmacological applications. 2D Interactions of Spinasterol 2D interactions are critical for analyzing the bioavailability and toxicity of compounds derived from the spider Arania Spinosa. Utilizing SwissADME, we will evaluate these interactions and determine their potential impact on pharmacology, offering an in-depth understanding of the pharmacological modulation of spinasterol along with its beneficial effects in biological contexts. Molecular Dynamics A thorough examination of molecular dynamics concerning spinasterol's interactions with \u003cstrong\u003eCCR2, NOX4\u003c/strong\u003e, and \u003cstrong\u003ePARP\u003c/strong\u003e over a duration of 100 nanoseconds (ns) provides a solid framework for rigorously assessing the stability of the complexes formed between these entities. This comprehensive analysis aims to identify the underlying mechanisms and interactions that directly govern the ligand's affinity for these specific protein targets. These findings are crucial in determining whether spinasterol could effectively serve as an inhibitor influencing significant pathological processes such as inflammation (via \u003cstrong\u003eCCR2\u003c/strong\u003e), oxidative stress (via\u0026nbsp;\u003cstrong\u003eNOX4\u003c/strong\u003e), and excessive apoptosis (via PARP). Each of these pathological processes is likely exacerbated by excessive and continuous alcohol consumption, further heightening the urgent need for effective potential treatments. The assessment of Root Mean Square Deviation (RMSD) serves as an essential method for measuring atomic position variations within the complex, demonstrating that all three receptors maintain stable structures throughout the entire 100 ns simulation. Observed fluctuations range notably from 1 to 3 Å, clearly indicating that in the presence of spinasterol, no significant disruptions occur in their initial conformation, thus reinforcing the notion of a stable and enduring interaction within the biological context. Moreover, the RMSD of the ligand itself remains relatively constant throughout the analysis, indicating firmly that spinasterol remains securely anchored within the active site of each receptor, without any notable dissociation recorded during the whole simulation procedure. The rationale supporting the observed stability rests upon a meticulous examination of the Root Mean Square Fluctuation (RMSF), which corroborates prior conclusions by revealing the presence of rigid α-helices that are less prone to flexibility within the three receptors. In contrast, more pronounced fluctuations occur in the extracellular and intracellular loops, which are inherently more flexible and play a dynamic role within the biological functions and signaling capabilities of the proteins. Furthermore, an in-depth analysis of protein-ligand contacts sheds light on a diverse array of crucial interactions necessary for effectively maintaining spinasterol within the active sites of the three studied receptors. Hydrophobic interactions, predominantly prevalent within the complexes, lead to strong bonds with apolar residues located inside the binding cavities, ensuring a durable and robust retention of the ligand along with the interactions established. Additionally, transient hydrogen bonds with certain polar residues further enhance the positioning and optimal anchoring of spinasterol within the complex. Additionally, the identification of π-π stacking and π-cation interactions with aromatic residues contributes substantially to the stabilization of the complex, a phenomenon particularly remarkable with the NOX4 and PARP receptors. Furthermore, water bridges have been detected in each complex, demonstrating that water molecules play a facilitatory role, indirectly contributing to the interaction of spinasterol with the target receptors and indicating a significant stabilization effect under simulated physiological conditions. The analysis of the duration of interactions reveals that several of these contacts are maintained for over 70% of the simulation period, thus attesting to spinasterol's high affinity for the three examined receptors. Notably, the spinasterol-CCR2 interaction is distinguished by prevailing hydrophobic interactions, accompanied by some transient hydrogen bonds, thus ensuring a stable anchor for the ligand without disturbing the initial conformation of the receptor. This strong interaction could potentially lead to meaningful modulation of CCR2 activation, consequently contributing to reducing excessive inflammation, a critical process in alcohol-induced cellular injuries suffered by tissues. Regarding the interaction with NOX4, it is noteworthy that this enzyme, involved significantly in free radical production, demonstrates a strong functional affinity for spinasterol, supported by hydrophobic interactions and π-π stacking, potentially leading to decreased excessive oxidative stress production and protecting cells from damage induced by alcohol in a pathological context. In the case of PARP, this enzyme, which plays a vital role in DNA repair and apoptosis induction, sees its interaction stabilized through hydrophobic interactions, stabilizing hydrogen bonds, and further π-π stacking interactions, suggesting that spinasterol might indeed play a key role in modulating PARP activation and thereby contribute significantly to preventing excessive apoptosis. The evaluation of Ligand RMSF for the three complexes indicates that atomic fluctuations of spinasterol remain low, thereby confirming its impressive conformational stability throughout the simulation. Moreover, the analysis of the ligand's torsion profile highlights that internal rotations of spinasterol are limited, thus ensuring an optimal configuration for its interaction with the three target receptors. To accurately illustrate these results concerning interactions and dynamics, several illustrative figures will be necessary: - The RMSD graph (for the proteins and the ligand) clearly demonstrating the consistent stability of the complex across the simulation.\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e- The RMSF graph (for the proteins) highlighting the observed fluctuations and rigidity in the CCR2, NOX4, and PARP receptors. - The protein-ligand contact graph showing the frequency and nature of the established interactions, visualizing how spinasterol engages with the active sites.\u003c/p\u003e\u003cp\u003e- A 3D representation of the complexes displaying hydrogen bonds, hydrophobic interactions, and water bridges within the complexes to visualize the interaction landscapes accurately. - Lastly, the ligand’s torsion profile, aimed at confirming its conformational stability in the context of interactions with the receptors, providing a comprehensive understanding of its structural integrity. In conclusion, the results unequivocally confirm that spinasterol establishes stable and persistent interactions with \u003cstrong\u003eCCR2, NOX4\u003c/strong\u003e, and \u003cstrong\u003ePARP\u003c/strong\u003e, indicating a significant inhibitory potential on these targets, all associated with alcohol-induced cellular damage. Its strong affinity relies primarily on hydrophobic and π-π stacking interactions, augmented by hydrogen bonds and water bridges, ensuring a stable anchoring within the active sites of the three receptors. To quantify these observations and precisely assess the binding affinity between spinasterol and each receptor, further energetic analysis employing MM-PBSA/MM-GBSA methods could be pursued to complement this critically important study. These results firmly position spinasterol as a promising candidate for modulating various pathological mechanisms associated with alcoholism, paving the way for more in-depth experimental and pharmacological research in the evolving future. The following figures illustrate comprehensively everything discussed above, enabling a visual understanding of the interactions and dynamics involved.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis in silico study highlights the potential of \u003cem\u003eArgania spinosa\u003c/em\u003e (argan oil) metabolites as inhibitors of key receptors involved in alcohol-induced toxicity, specifically NOX4 (NADPH Oxidase 4), PARP (Poly ADP-ribose Polymerase), and CCR2 (C-C Motif Chemokine Receptor 2). Through a multi-faceted computational approach incorporating ADMET analysis, molecular docking, and molecular dynamics simulations, the study identified spinasterol as the most promising bioactive compound, demonstrating high binding affinity and stability across all three target receptors. These findings suggest that argan oil metabolites could serve as natural therapeutic agents to mitigate oxidative stress, inflammation, and apoptosis associated with excessive alcohol consumption.\u003c/p\u003e\u003cp\u003eA key contribution of this study is the detailed characterization of molecular interactions, revealing that hydrophobic interactions, π-π stacking, and hydrogen bonding play crucial roles in receptor inhibition. The results reinforce the potential of natural bioactive compounds in drug discovery and therapeutic intervention against alcohol-induced pathologies. However, further experimental validation through in vitro and in vivo studies is required to confirm these computational findings and elucidate the precise biological mechanisms underlying these interactions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFuture Perspectives\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eThis research lays the groundwork for several promising avenues of future investigation\u003c/strong\u003e:\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp; \u0026nbsp;Experimental Validation:\u0026nbsp;\u003c/strong\u003eFuture studies should prioritize in vitro assays and in vivo models to confirm the efficacy of spinasterol and other argan oil metabolites in modulating NOX4, PARP, and CCR2 activity under alcohol-induced oxidative stress conditions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp; \u0026nbsp;Optimization and Drug Development:\u0026nbsp;\u003c/strong\u003eStructural modifications of spinasterol and related metabolites should be explored to enhance their pharmacokinetic properties, increase bioavailability, and improve target specificity, paving the way for the development of novel natural therapeutic agents.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e3.\u0026nbsp; \u0026nbsp;Development of Natural Therapeutics:\u003c/strong\u003e Given the favorable pharmacological profile of argan oil metabolites, efforts should be directed toward the formulation of nutraceuticals or dietary supplements designed to prevent or alleviate alcohol-related hepatic and neurological damage.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp; \u0026nbsp;Integration into Preventive and Therapeutic Medicine:\u0026nbsp;\u003c/strong\u003eThis study underscores the potential for integrating argan oil metabolites into preventive healthcare strategies for alcohol-induced liver fibrosis, neurodegenerative disorders, and chronic inflammatory conditions, contributing to broader public health initiatives.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e5.\u0026nbsp; \u0026nbsp;Exploration of Additional Therapeutic Targets:\u0026nbsp;\u003c/strong\u003eBeyond alcohol-related toxicity, the antioxidant and anti-inflammatory properties of these bioactive compounds warrant further investigation into their potential applications in metabolic disorders, cardiovascular diseases, and neurodegeneration, thereby expanding their therapeutic scope\u003c/p\u003e\u003cp\u003eOverall, this study establishes a scientific foundation for the exploration of \u003cem\u003eArgania spinosa\u003c/em\u003e metabolites as potential modulators of oxidative and inflammatory pathways. The insights gained from this work provide a strong rationale for future experimental and translational research, aiming to harness natural bioactive compounds for innovative and sustainable therapeutic interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eWe, the undersigned, declare that each author has made a substantial contribution to the development of the study entitled:Manuscript Title:In Silico Study of Argan Oil Metabolites: Evaluation of Their Potential to Inhibit Key Receptors Activated by Excessive Alcohol Consumption and Involved in Cell DeathContribution Breakdown:Ayoub Bekkouch: Study design and conception, in silico analyses (molecular docking, ADMET, molecular dynamics), data interpretation, manuscript writing, and revision.Oussama Bekkouch: Contribution to methodology, validation of results, assistance in data analysis, and manuscript drafting.Anas Ziani: Literature review, assistance in writing, and manuscript formatting.Nour E. Bentouhami: Data collection and analysis, assistance in preparing figures and tables.Oumaima Abouyala: Supervision of bioinformatics analyses, critical manuscript review, and validation of employed methodologies.El Arbaoui Marouane: Contribution to result interpretation and technical review.Hamzaoui Abdelghafour: Support in statistical analyses and validation of in silico results.Aboubaker El Hesni: Contribution to discussion and critical analysis of experimental data.Abdelhalem Mesfioui: Scientific supervision, critical manuscript review, and final approval of the submitted version.El Mostafi Hicham: Overall project supervision, methodological coherence oversight, and contribution to clinical and pharmacological aspects.All authors have read and approved the final version of the manuscript and accept full responsibility for the published content.We also confirm that there are no conflicts of interest related to this study and that the presented work is original and has not been published or submitted elsewhere.Issued in Oujda, on 17/02/2025\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAbbassi, A. 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Ethanol and acetaldehyde in alcoholic cardiomyopathy: from bad to ugly en route to oxidative stress. \u003cem\u003eAlcohol\u003c/em\u003e, \u003cem\u003e32\u003c/em\u003e(3), 175\u0026ndash;186.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 2","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"argan oil metabolites, cell death, NOX-4, PARP, CCR2, ADME analysis, Docking, Molecular dynamic ","lastPublishedDoi":"10.21203/rs.3.rs-6049168/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6049168/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eExcessive alcohol consumption is a well-established cause of liver injury and neurodegeneration, driven by oxidative stress, inflammation, and apoptosis. This study explores the potential of Argania spinosa (argan oil) metabolites as natural inhibitors of key receptors involved in alcohol-induced cellular damage: NOX4 (NADPH Oxidase 4), PARP (Poly ADP-ribose Polymerase), and CCR2 (C-C Motif Chemokine Receptor 2). Using in silico approaches, including molecular docking, ADMET analysis, and molecular dynamics simulations, we systematically evaluated the interactions between twenty previously reported argan oil metabolites and these receptors.\u003c/p\u003e\n\u003cp\u003eAmong the analyzed compounds, spinasterol emerged as the most promising bioactive molecule, demonstrating high binding affinity and structural stability within the receptor active sites. Molecular interaction analysis revealed strong hydrophobic interactions, π-π stacking, and hydrogen bonding, contributing to receptor inhibition. These findings suggest that spinasterol could modulate inflammatory and oxidative pathways, reducing alcohol-induced cellular stress.\u003c/p\u003e\n\u003cp\u003eThis study underscores the potential of argan oil metabolites as natural therapeutic agents for preventing and mitigating alcohol-related pathologies. Future in vitro and in vivo investigations are necessary to validate these computational results and explore the translational potential of these compounds in clinical settings. The findings contribute to advancing plant-based drug discovery and natural pharmacological interventions for alcohol-induced disorders.\u003c/p\u003e","manuscriptTitle":"In Silico Study of Argan Oil Metabolites: Evaluation of Their Potential to Inhibit Key Receptors Activated by Excessive Alcohol Consumption and Involved in Cell Death","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-21 07:10:41","doi":"10.21203/rs.3.rs-6049168/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5b8f5a4f-b69e-47ae-a667-580d92745548","owner":[],"postedDate":"February 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-20T01:38:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-21 07:10:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6049168","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6049168","identity":"rs-6049168","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}