Quercetin and Kaempferol as Potential Modulators of Dopaminergic, Serotonergic, and Estrogenic Receptors: Computational Insights into Female Reproductive Health

Quercetin and Kaempferol as Potential Modulators of Dopaminergic, Serotonergic, and Estrogenic Receptors: Computational Insights into Female Reproductive Health | 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 Quercetin and Kaempferol as Potential Modulators of Dopaminergic, Serotonergic, and Estrogenic Receptors: Computational Insights into Female Reproductive Health Muhammed Robiu ASINMI, AbdulAzeez Olamilekan Elemosho, Mansurat Bolanle FALANA, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8627630/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Natural polyphenols like kaempferol and quercetin draws interest because of their ability to interact with multiple receptors. This study determines the pharmacokinetic characteristics, stability, and binding dynamics of quercetin and kaempferol. Methods Protein and ligand structures were obtained from the Protein Data Bank and PubChem, respectively. LigPrep and Protein Preparation Wizard (Schrödinger Suite 2023) were used to prepare the ligands and protein, respectively. Docked complexes were prepared subjected to 100 ns MD simulations using Desmond. Both ligands formed stable complexes. Results With variations within 1–3 Å range, the RMSD values for quercetin and kaempferol stabilized at about 50ns, and some earlier. RMSF plots demonstrated consistent interactions with important residues and decreased mobility in ligand-binding areas. Throughout the simulation, PHE, LEU and TRP formed persistent hydrophobic interactions, HIS, SER, THR and ASN formed polar interactions stable hydrogen bonds while GLU and ASP contributes negatively charged interactions. Both kaempferol and quercetin shows excellent metabolic stability and drug-likeness. Kaempferol, shows better ADMET properties and interaction consistency. Conclusions Due to the presence of stable and prolonged activation of ESR2, HTR2C and SLC6A3 the therapeutic value of kaempferol and quercetin in enhancing the sexual health of women is confirmed, with kaempferol showing better profile. ADMET Kaempferol Molecular Dynamics Phamacokinetics Quercetin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 1.0 Introduction Plant-based natural compounds, have been used extensively to treat various pathological processes due to their superior tolerability and higher bioavailability when compared to synthetic drugs 1 . Flavonoids and non-flavonoids are two significant groups of phenols. Flavonoids, which are frequently present in fruits, vegetables, and herbs, have a variety of therapeutic uses, including antiviral, anti-inflammatory, cytotoxic, antioxidant, cardioprotective, and neuroprotective effects 2,3 . Fruits, vegetables, and herbs are frequently rich in flavonoids, which are chemicals with a variety of therapeutic uses, including antiviral, anti-inflammatory, cytotoxic, antioxidant, cardioprotective, and neuroprotective effects 2,3 . The majority of these flavonoids are related to the steroid sex hormone 17β-estradiol 4 . Thus, phytoestrogenic flavonoids affect gene expression, cellular communication, and physiological responses by interacting with the ER2, SLC6A3, HTR2A and CNR2 and potentially imitating, modifying, or blocking their actions 5 . It has been proposed that a number of phytoestrogens attach to and activate ERα and ERβ 6 . The research on quercetin's impact on ERs, however, has conflicting findings. See Fig. 1 for Kaempferol (KAE) structure 7 . A phytoestrogen with possible health benefits, quercetin is a member of the flavonol subclass of flavonoid chemicals. Many fruits and vegetables contain it, although onions are the main source 8 . Quercetin may have a variety of biological effects, such as antimicrobial, anticancer, antihypertensive, anti-inflammatory, and antioxidant effects, according to a number of in vitro and in vivo investigations 9 . According to some research on quercetin's estrogenic activity, it only has anti-estrogenic effects on the estrogen-sensitive breast cancer cell line MCF-7 10 . However, other studies have discovered that quercetin has dose-dependent effects that are both estrogenic and anti-estrogenic (Fig. 2) 11 . In females, the ovaries and placenta generate the majority of estrogen (Fig. 3), a steroid molecule that has significant modulatory effects on both physiological and pathological processes 12 . According to Çiftci 13 , it affects the development, differentiation, and operation of several target organs, including the reproductive organs of both sexes. While estrogen shortage has been linked to osteoporosis, neurological illnesses, cardiovascular disease, and obesity 14,15 , estrogen is involved in the development of breast, ovarian, endometrial, and prostate cancer 16 . When estrogen binds to the estrogen receptors (ERs), it causes a number of cellular alterations. ERα and ERβ are the two primary types of ERs. According to Klinge et al. 17 , ERs are ligand-dependent transcription factors that facilitate the normal biological activities of estrogens by controlling gene transcription through estrogen response elements (EREs). However, a number of conditions, including different types of cancer and gynecological conditions like polycystic ovary syndrome and endometriosis, can be brought on by aberrant ER signaling 18 . Numerous brain activities depend on dopamine (DA) 19,20 , and it is also linked to inflammation 21,22 , heart failure 23,24 , cancer 25,26 , circadian rhythms, and sleep 27,28 . Given that the human DA transporter protein (hDAT) in the plasma membrane is one of the primary regulators of synaptic DA transmission 29 , genetic variation in the coding gene SLC6A3 in human chromosome 5 (chr5) may impact SLC6A3 function, change the density of hDAT, DA reuptake activity, and the dynamics of DA neurotransmission, all of which can contribute to pathophysiology in the central (CNS) and peripheral nervous systems. The central nervous system expresses at least 14 different subtypes of serotonin (5-hydroxytryptamine; 5-HT) receptors 30 . Biochemical studies show that pharmacological modulation of the 5-HT2C receptor considerably influences dopamine transmission in the dorsal striatum 31 , despite electrophysiological results supporting a preferential regulation of mesocorticolimbic dopamine pathways by the 5-HT2C receptor subtype 32 . 5-HT2C receptors have been demonstrated to give projection neurons in the basal ganglia's output regions, such as the substantia nigra pars reticulate (SNr) excitatory drive 33 . It is believed that all of the main drugs of abuse, including as opiates and psychomotor stimulants, work by facilitating mesolimbic dopamine transmission. For instance, morphine causes mesolimbic dopamine neurons to be excited mainly by lowering GABAergic inhibition of dopaminergic cells 34 , whereas cocaine increases dopamine availability in the synapse by blocking the transporter mediating dopamine reuptake into the presynaptic terminal 35 . Therefore, it is evident that pharmacological medications that affect dopamine transmission may be able to modify the behavioral and reinforcing effects of drugs of abuse. The 5-HT receptor subtypes that are known to alter mesolimbic dopamine activity, including the 5-HT2C receptor, have received a lot of attention in this context. The stability and mechanism of binding of quercetin and kaempferol, two flavonols, on the receptors of reproductive importance are poorly understood and to develop more effective and selective medications for this novel possible target, ligand binding mechanisms must be clarified. To fully understand this process, molecular dynamics techniques can offer a powerful research method. Using this method, we can forecast how the phytochemicals from A. garckeana could interact with significant biological targets linked to the sexual health of women. Therefore, the purpose of this study is to present reliable data about the mode of action and binding stability of quercetin and kaempferol to selected receptors. 2.0 Materials Hardware and Software Requirements Dell Latitude 3190 workstation with Intel(R) Pentium(R) Silver N5000 CPU @ 1.10 GHz, Intel(R) UHD Graphics 605 graphics card with hardware stereo, 8 GB RAM, and 120 GB hard drive. Molecular docking was done using the Schrödinger Suite. Databases and Receptor Structures Three-dimensional structures of target hormones and neurotransmitter receptors were obtained using the Protein Data Bank (PDB) ( https://www.rcsb.org/ ). Chemical structures and information about the compounds were retrieved using PubChem ( https://pubchem.ncbi.nlm.nih.gov/ ). 2.1 Methods Ligand preparation The PubChem database provided the two-dimensional structures of quercetin and kaempferol. According to Brooks et al. 36 , the ligand library was then produced using Ligprep (Schrodinger suite version 2023) and put into a docking program (Maestro). Protein preparation The proteins used in this investigation were sourced from the "Protein Data Bank." Each protein complex in this investigation was prepared using the Protein Preparation workflow (PrepWizard) in Maestro (Maestro, 2023), as explained by Madhavi et al. 37 . Molecular Docking The Glide module was started in Maestro when the protein and ligand were ready. It was possible to identify the protein's binding location by sampling the ligand's rotatable bonds and torsional degrees of freedom. Glide's Extra Precision (XP) mode was utilized to dock the ligand into the protein's binding site and produce potential binding poses. Induced fit docking software on maestro schrodinger was used for induce fit docking (IFD). As described by Brooks et al. 36 , only the top-ranked poses were used for molecular dynamics. Molecular Dynamics (Maestro –Desmond) Molecular Dynamics (MD) simulations were performed using the technique described by Anand et al. 38 . For MD setup, the docked ligand-receptor complex from IFD was utilized. To neutralize and solvate the system, counterions and water molecules were added to the simulation box. The force field of choice was determined to be OPLS 4. To observe the molecule's dynamic behavior, the system was simulated for 100 nanoseconds. A simulated interaction diagram was used to assess the generated trajectory files. Pharmacokinetics (PK) Pharmacokinetic (PK) parameters were analyzed using the Patil et al. 39 approach. The compound's ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics were predicted using Schrödinger's QikProp. 3.0 Results Top 3 Induced Fit Docking Score of Quercetin and Kaempferol in Receptor Targets Table 1 presents the Induced Fit Docking Scores of quercetin and kaempferol. Quercetin exhibited strong docking scores with CNR2 (Cannabinoid Receptor 2), with the top three scores ranging from − 901.69 to -902.03 kcal/mol, with ESR2 (Estrogen Receptor Beta), within a range of -516.51 to -516.78 kcal/mol. Kaempferol, similarly, demonstrated substantial binding to CNR2, (-898.92 to -899.28 kcal/mol), then ESR2, (-515.94 and − 516.48 kcal/mol). The SLC6A3 (Dopamine Transporter) receptor, shows the highest docking score of -1068.37 kcal/mol. Figure 4 shows heat maps of interaction between the ligand and receptor sites. Root Mean Square Deviation (RMSD) Analysis of Quercetin and Kaempferol in Complex with Receptors The Root Mean Square Deviation (RMSD) was analyzed for both quercetin and kaempferol in complex with receptors. Some minor deviations were observed at the early stage of simulations. However, both quercetin and kaempferol had RMSD values for the protein and ligands with fluctuations within the range of 1–3 Å. The RMSD values for both the protein and ligand stabilized at 50ns in ESR2-Quercetin complex and 20ns in ESR2- Kaempferol complex, 70ns in HTR2C-Quercetin complex, 0ns in SLC6A3-Kaempferol complex, 20ns in CNR2-Kaempferol complex while CNR2-Quercetin complex does not reach equilibrium (Fig. 5). Root Mean Square Fluctuation (RMSF) Analysis of Quercetin and Kaempferol in Complex with Receptors Protein RMSF plot revealed that the N-terminal and C-terminal loops, exhibited higher fluctuation. In contrast, secondary structure elements such as alpha-helices (highlighted with a red background) and beta-strands (highlighted with a blue background) showed lower RMSF values. The loop regions exhibited moderate RMSF values, showing fluctuation not as significant as the N- and C-terminal regions. The protein residues interacting with the ligand were identified and marked with green-colored vertical bars on the RMSF plot. These residues showed lower RMSF values compared to the non-interacting residues. This observation was consistent for both quercetin and kaempferol. (Fig. 6). Table 1 Top 3 Induced Fit Docking Score of Quercetin and Kaempferol in Receptor Targets S/N Target Phytochemicals Induced Fit Docking Score (kcal/mol) S/N Target Phytochemicals Induced Fit Docking Score (kcal/mol) 1 ESR2 Quercetin -516.78 4 CNR2 Quercetin -902.03 Quercetin -516.69 Quercetin -901.80 Quercetin -516.51 Quercetin -901.69 Kaempferol -516.48 Kaempferol -899.28 Kaempferol -515.94 Kaempferol -898.95 Kaempferol -515.94 Kaempferol -898.92 2 SLC6A3 Kaempferol -1068.37 5 6 HTR2C Quercetin -790.59 Kaempferol -1068.34 Quercetin -790.57 Kaempferol -1067.97 Quercetin -790.43 Protein–Ligand Interaction Timeline, Protein–Ligand Interaction Profiles and Ligand–Protein Contacts The timeline depicts hydrogen bonds, hydrophobic contacts, ionic interactions, and water bridges. (Figs. 7 and 8). Hydrogen bonds (H-bonds) were observed consistently across several complexes, with backbone and side-chain atoms from both protein and ligand participating. Hydrophobic contacts, including π–cation and π–π interactions, were frequently observed, especially in complexes involving aromatic or aliphatic moieties on the ligand. These contacts were primarily maintained with nonpolar side chains of residues located in the hydrophobic core of the receptor binding sites. Ionic interactions, which are common in some systems including charged residues such as Asp, Glu, Lys, and Arg, were absent. Water bridges provided extra stability to the complexes by acting as mediators in indirect hydrogen bonding (Fig. 9). Protein-ligand contact analysis demonstrated that quercetin maintained stable connections with critical residues in the ESR2 binding pocket throughout the simulation. Notably, GLU 305 exhibited consistent charged (negative) interactions for 73% and 76% of the simulation time. A polar interaction was also maintained with HIS 475 for 63% of the trajectory, while hydrophobic contact with PHE 356 occurred in 38% of the frames. For Kaempferol, HIS 475 showed a polar interaction involving a water bridge in 78% of the simulation, and GLU 305 sustained a water-mediated charged (negative) interaction in 77% of the frames. Additionally, PHE 356 contributed hydrophobic contacts in 61% of the trajectory via direct interaction and 57% through water mediation (Figs. 10 and 11). Pharmacokinetics In comparison to quercetin (18.199, score of 2 and 51.649%, 6.511, -5.544 respectively), kaempferol demonstrated significantly higher Caco-2 cell permeability (51.24), human intestinal absorption (3), predicted percentage of oral bioavailability (63.637%), MDCK cell permeability (19.934), and better skin permeability in QPlogKp value (-4.641). Compared to quercetin (5), kaempferol (4) has a significantly smaller number of rotatable bonds. Compared to quercetin (-0.343), kaempferol showed a greater projected plasma protein binding (QPlogKhsa: -0.191) in the distribution profile. Both compounds had low blood-brain barrier permeability (QPlogBB) (-1.893 vs. -2.419), and their CNS scores indicated that they were expected to be inactive. In comparison to 302.24 g/mol, kaempferol had a lower molecular weight (286.24 g/mol) and a smaller molecular volume (844.89 vs. 867.28). The polarity of quercetin is greater (4.721 vs. 4.456). With minor differences in electrical and structural characteristics, quercetin and kaempferol had metabolic profiles that were mostly similar. The surface area to electron density ratio (dip257; 0.0235) of quercetin was somewhat greater than that of kaempferol. Kaempferol's ionization potential (IP) is 9.009 eV, while quercetin's is 8.984 eV. Compared to kaempferol (0.57 eV), quercetin had a slightly higher electron affinity (EA) of 0.623 eV. Kaempferol was expected to produce four metabolic products, whereas quercetin was expected to produce five. Both compounds had very good profiles in terms of toxicity, excretion, and overall drug-likeness. Neither compound violated Lipinski's or Jorgensen's criteria, nor did they show any reactive functional groups. The properties of both compounds were within the recommended physicochemical space (#stars = 0). Quercetin (-5.109) and kaempferol (-5.201) both showed low and comparable predicted inhibition of the hERG potassium channel. Kaempferol had a higher human clearance (measured by QPlogPo/w) than quercetin (0.367) (Table 2 ). Table 2 Evaluation of ADMET Parameters for Quercetin and Kaempferol S/N Parameter Quercetin Kaempferol 1. Caco-2 Permeability (QPPCaco) a 18.199 51.24 2. HIA (HumanOralAbsorption) a 2 3 3. Oral Bioavailability (% Human Oral Absorption) a 51.649 63.637 4. Number of rotatable bonds (#rotor) a 5 4 5. Solvent-accessible surface area (SASA) a 519.28 507.45 6. MDCK cell permeability (QPPMDCK) a 6.511 19.934 7. Skin permeability (QPlogKp) a -5.544 -4.641 8. Predicted oral absorption (HumanOralAbsorption) a 2 3 9. Plasma Protein Binding (QPlogKhsa) b -0.343 -0.191 10. BBBP Probability (QPlogBB) b -2.419 -1.893 11. CNS activity (CNS) b -2 -2 12. Molecular weight (mol MW) b 302.24 286.24 13. Dipole moment (dipole) b 4.721 4.456 14. Molecular volume (volume-1) b 867.28 844.89 15. Predicted binding to serum albumin (QPlogKhsa) b -0.343 -0.191 16. Surface Area / Electron density (dip^2/V) c 0.0257 0.0235 17. Ionization potential (IP eV) c 8.984 9.009 18. Electron affinity (EA eV) c 0.623 0.57 19. Number of predicted metabolic products (#metab) c 5 4 20. hERG Inhibition (QPlogHERG) d -5.109 -5.201 21. Predicted blocking of hERG channels d -5.109 -5.201 22. Number of reactive functional groups d 0 0 (rtvFG) 23. Lipinski Rule Violations d 0 0 24. Jorgensen Rule Violations d 0 0 25. Properties outside recommended range d 0 (#stars) 0 (#stars) 26. Human Clearance (QPlogPo/w) d 0.367 1.041 27. Blockage of hERG K + channels d -5.109 -5.201 4. 0 Discussion Plants, fruits, vegetables, and leaves naturally contain phenolic molecules called flavonoids, which are phytochemicals with a variety of therapeutic uses, including antiviral, anticancer, antioxidant, anti-inflammatory, neuroprotective, cardioprotective, and aphrodisiac qualities 2 , 40 , 11 . According to earlier network pharmacology and molecular docking studies, estrogen receptor beta plays a significant role in improving the sexual health of women. Induced Fit docking studies gave stronger proof of how well these plant compounds binds to their intended targets in the body. It is particularly intriguing to see how incredibly strongly quercetin and kaempferol bind to SLC6A3, which modifies dopamine availability in the brain 41 . Both Quercetin and Kaempferol binds tightly to the CNR2 which are extremely significant because estrogen receptor beta and cannabinoid receptor 2 are known to be essential for sexual behavior and reward perception. Strong binding of Quercetin with HTR2C receptor may exerts both tonic and phasic modulation of central dopamine transmission via activation of 5-HT2C receptors as several lines of evidence has indicated. Both Quercetin and Kaempferol showed a strong binding (although the least of all) with ESR2. This also suggests that Quercetin could act like phytoestrogens, mimicking or adjusting the effects of our body's natural estrogen. Ruan et al. 42 reported kaempferol as an effective modulator in endometrial cancer treatment. Values of RMSD of quercetin, kaempferol and that of the receptor were fairly constant between 1-3A except CNR2-Quercetin complex which failed to stabilize. It means that the protein structures with Quercetin and Kaempferol generally remained stable throughout the simulation and stabilized. RMSF demonstrates weather the receptor-protein residues are flexibility, providing information about the local movements and change of some region within the protein chain 43 . The C-terminal and N-terminal loops were more volatile, which is typical in protein dynamics. Secondary structure elements with lower RMSF such as beta-strands and alpha-helices, however, were not fluctuating and were more rigid. The helices and strands like most components of secondary structure did not show signs of breaking apart during the simulation. Throughout the simulation courses, some patterns of contact are traced by the depiction of the interaction of proteins and ligands 44 . In complexes involving aromatic or aliphatic moieties on the ligand, hydrophobic contacts, such as π–cation and π–π interactions, were commonly observed. Nonpolar side chains of residues found in the hydrophobic core of the receptor binding sites were mostly responsible for maintaining these interactions. Water molecules acted as mediators in indirect hydrogen bonding to create water bridges, which gave the complexes more stability. Quercetin formed consistent bonds with important residues in ESR2, HTR2C, SLC6A3 and CNR2 binding pocket. For over 70% the simulation period, respectively, Hydrophobic interactions with PHE, LEU, TRP were very instrumental in ensuring the stability of the complex. GLU, ASP demonstrated continuous charged (negative) interactions, suggesting robust and potentially dual connections, both water-mediated and direct. For over 70% of the trajectory, a polar association was also maintained with HIS, SER, THR. These results point to a polar and charged interaction-dominated, somewhat constant, and unique interaction profile between quercetin and ESR2. In comparison to quercetin, the greater frequency and diversity of interactions seen with kaempferol point to a stronger and possibly more adaptable binding profile. The impact of these interactions was also found by Lotfi et al. 45 , indicating that natural flavonoids may have therapeutic potential for treating osteoporosis by targeting ERs. Kaempferol showed exceptional qualities in terms of absorption across the majority of assessed criteria. It showed noticeably increased Caco-2 cell permeability, suggesting improved intestinal absorption potential, improved intestinal absorption in humans and a higher estimated oral bioavailability percentage (63.637%). Kaempferol has a smaller number of rotatable bonds suggesting a stiffer structure that would promote permeability. Additionally, kaempferol showed improved skin permeability and increased MDCK cell permeability, superior oral absorption profile and distribution profile. Although both flavonol were expected to be inactive in the central nervous system, kaempferol had a significantly less negative value, indicating somewhat higher CNS penetration, despite the fact that both compounds had poor blood-brain barrier permeability. Furthermore, Kaempferol possessed two advantageous characteristics for distribution: a lower molecular weight and a smaller molecular volume. This is consistent with other research that has been done on the bioactivity, therapeutic potential, and bioavailability of quercetin and kaempferol 46 , 47 . With minor differences in electrical and structural characteristics, quercetin and kaempferol had metabolic profiles that were mostly similar. Similar tendencies to lose electrons were indicated by the nearly identical ionization potential (IP) values. Similarly, quercetin's electron affinity (EA) was marginally higher than kaempferol's, indicating a marginally higher capacity to take up electrons. Quercetin was expected to produce five metabolic products in terms of metabolic stability, while Kaempferol produced four, suggesting that Quercetin may have a little higher metabolic complexity. Oliveira et al. 48 used LC-ESI MS to examine the metabolism of quercetin and kaempferol by rat hepatocytes. They discovered that both flavonoids were extensively metabolized (98.8 +/- 0.1% and 81.0 +/- 5.1%, respectively, n = 4), with two kaempferol glucuronides and four quercetin glucuronides detected after incubation. Both compound obeyed Lipinski's and Jorgensen's rules and neither displayed any reactive functional groups, highlighting their adherence to accepted drug-likeness standards. Furthermore, neither molecule exhibited any characteristics outside of the suggested physicochemical area (#stars = 0). Both quercetin and kaempferol showed modest and comparable predicted blockage of the hERG potassium channel, a crucial indicator of cardiotoxicity, indicating a minimal risk of hERG-mediated deleterious cardiac consequences. Compared to quercetin, kaempferol had a greater human clearance (measured by QPlogPo/w), suggesting a possible quicker rate of excretion or metabolic turnover. Ali et al. 49 used pharmacokinetic and docking software to examine the druggability and binding affinities of quercetin and kaempferol towards a number of antidiabetic targets in order to study the multi-targeting antidiabetic potential of these drugs. Both quercetin and kaempferol have favorable ADMET profiles, low predicted cardiotoxicity (low hERG inhibition), and conform to Lipinski's and Jorgensen's rules. Conclusion This study demonstrates that the flavonoids quercetin and kaempferol exhibit strong multi-target binding affinities toward key receptors implicated in female sexual health, including ESR2, HTR2C, SLC6A3, and CNR2. Molecular docking and dynamic simulations confirmed stable receptor–ligand interactions dominated by hydrophobic, polar, and charged contacts. ADMET and drug-likeness analyses revealed favorable pharmacokinetic profiles, with kaempferol showing superior absorption and distribution characteristics. Both compounds complied with established safety and drug-likeness rules, exhibiting low cardiotoxic risk. These findings support the therapeutic potential of quercetin and kaempferol as promising phytoestrogenic candidates for sexual health modulation. Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request Competing interests The authors declare that they have no competing interests Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions Investigation, methodology, data curation, writing—original draft preparation, M.R.A., A.O.E, and M.B.F; validation, visualisation, resources, software, Z.O.B., M.A.D. and K.O.S.; conceptualisation, writing—review and editing, M.A.A and Q.O.N. All authors have read and agreed to the published version of the manuscript. Acknowledgements The authors appreciate the contribution of Mr. Dele Aiyepeku of the Department of Biochemistry, University of Ilorin, Ilorin, Nigeria, for the technical assistance provided in the course of this study. ORCID Muhammed Robiu Asinmi, ORCID: https://orcid.org/0000-0003-4886-4687 AbdulAzeez Olamilekan Elemosho ORCID: https://orcid.org/0000-0001-6480-7995 Mansurat Bolanle Falana, ORCID: https://orcid.org/0000-0003-4370-3059 Zainab Olajumoke Bello ORCID: https://orcid.org/0000-0002-9790-0472 Muhammad Ali DikwaORCID: https://orcid.org/0009-0002-7819-6683 Kamaldeen Olalekan Sanusi ORCID: https://orcid.org/0000-0002-9588-7710 Musbau Adewumi Akanji ORCID: https://orcid.org/0000-0003-4476-454X Quadri Olaide Nurudeen ORCID: https://orcid.org/0000-0001-5261-8679 References Patel, S., Chopra, S., Chaurasia, S., and Sarwat, M. (2022). Plant based bioavailability enhancers. Current Pharmaceutical Design 28 , 642–654. Ahmed, M., and Eun, J.B. (2018). 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Oliveira, E.J., Watson, D.G., and Grant, M.H. (2002). Metabolism of quercetin and kaempferol by rat hepatocytes and identification of flavonoid glycosides in human plasma. Xenobiotica 32 , 279–287. Ali, M., Hassan, M., Ansari, S.A., Alkahtani, H.M., Al-Rasheed, L.S., and Ansari, S.A. (2024). Quercetin and kaempferol as multi-targeting antidiabetic agents in a chemically induced type 2 diabetes mouse model. Pharmaceuticals 17 , 757. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 03 Apr, 2026 Reviewers agreed at journal 23 Mar, 2026 Reviewers invited by journal 10 Mar, 2026 Editor invited by journal 19 Feb, 2026 Editor assigned by journal 19 Jan, 2026 Submission checks completed at journal 19 Jan, 2026 First submitted to journal 17 Jan, 2026 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8627630","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":605214553,"identity":"530e4003-fe9b-4ae4-8524-06fe78d89856","order_by":0,"name":"Muhammed Robiu ASINMI","email":"","orcid":"","institution":"Al-Hikmah University","correspondingAuthor":false,"prefix":"","firstName":"Muhammed","middleName":"Robiu","lastName":"ASINMI","suffix":""},{"id":605214554,"identity":"2e02d52b-c153-48cc-8b5f-1013fbe1587c","order_by":1,"name":"AbdulAzeez Olamilekan Elemosho","email":"","orcid":"","institution":"Al-Hikmah University","correspondingAuthor":false,"prefix":"","firstName":"AbdulAzeez","middleName":"Olamilekan","lastName":"Elemosho","suffix":""},{"id":605214555,"identity":"edc02458-5fcb-48c4-94a6-151c1c35651f","order_by":2,"name":"Mansurat Bolanle FALANA","email":"","orcid":"","institution":"Al-Hikmah University","correspondingAuthor":false,"prefix":"","firstName":"Mansurat","middleName":"Bolanle","lastName":"FALANA","suffix":""},{"id":605214556,"identity":"7ee7f465-e5fd-4fb3-a34e-fd203b0b7efc","order_by":3,"name":"Zainab Olajumoke BELLO","email":"","orcid":"","institution":"Al-Hikmah University","correspondingAuthor":false,"prefix":"","firstName":"Zainab","middleName":"Olajumoke","lastName":"BELLO","suffix":""},{"id":605214557,"identity":"fe5c90c0-e154-414a-b1f2-546483a5d525","order_by":4,"name":"Muhammad Ali DIKWA","email":"","orcid":"","institution":"Federal University Dutse","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"Ali","lastName":"DIKWA","suffix":""},{"id":605214558,"identity":"402c7948-33b7-453c-abcc-6c99b202dfca","order_by":5,"name":"Kamaldeen Olalekan SANUSI","email":"","orcid":"","institution":"Al-Hikmah University","correspondingAuthor":false,"prefix":"","firstName":"Kamaldeen","middleName":"Olalekan","lastName":"SANUSI","suffix":""},{"id":605214559,"identity":"91ef733f-78c1-45de-97c0-5b71c72fe15d","order_by":6,"name":"Musbau Adewumi AKANJI","email":"","orcid":"","institution":"Kwara State University","correspondingAuthor":false,"prefix":"","firstName":"Musbau","middleName":"Adewumi","lastName":"AKANJI","suffix":""},{"id":605214560,"identity":"a9607a92-9293-4d44-9c62-a7fdb0009da0","order_by":7,"name":"QUADRI OLAIDE NURUDEEN","email":"data:image/png;base64,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","orcid":"","institution":"Al-Hikmah University","correspondingAuthor":true,"prefix":"","firstName":"QUADRI","middleName":"OLAIDE","lastName":"NURUDEEN","suffix":""}],"badges":[],"createdAt":"2026-01-17 17:38:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8627630/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8627630/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104665617,"identity":"0f14045c-eb34-4088-8b50-5f1f9ecd7b4a","added_by":"auto","created_at":"2026-03-15 15:31:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":107641,"visible":true,"origin":"","legend":"\u003cp\u003eChemical structure of Kaempferol. Kaempferol is a tetrahydroxyflavone, with the hydroxy groups distributed at positions 3, 5, 7, and 4′.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/0bd520a8157f588c41ac38f9.png"},{"id":104783233,"identity":"cc048dd4-bc5f-406f-9827-785fd4637f9b","added_by":"auto","created_at":"2026-03-17 07:58:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":95833,"visible":true,"origin":"","legend":"\u003cp\u003eChemical structure of quercetin. Quercetin is a pentahydroxyflavone, with hydroxyl groups at positions 3, 5, 7, 3′, and 4′.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/69ae8932f4a26111b08607ca.png"},{"id":104782176,"identity":"88632843-6262-42fd-a473-e9a999657cf4","added_by":"auto","created_at":"2026-03-17 07:56:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141472,"visible":true,"origin":"","legend":"\u003cp\u003eChemical structure of estrogen (17β-estradiol): 17β-estradiol is a primary endogenous estrogen and a steroid hormone with a characteristic four-ring cyclopentanoperhydrophenanthrene structure.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/ce5d7ab57e7e8f61a1ab89e5.png"},{"id":104665618,"identity":"07fc7eed-1b4e-43a1-8403-f82eff5b305b","added_by":"auto","created_at":"2026-03-15 15:31:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1194417,"visible":true,"origin":"","legend":"\u003cp\u003eHeat Map of Ligand Interactions with Receptor Residues\u003c/p\u003e\n\u003cp\u003e(a) Quercetin with ESR2; (b) Kaempferol with ESR2; (c) Quercetin with CNR2; (d) Kaempferol with CNR2; (e) Kaempferol with SLC6A3; (f) Quercetin with HTR2C.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/42503b1a1ab9b92916b322cb.png"},{"id":104782526,"identity":"6f4ebc66-fcdb-4bf5-905a-ba0f57afe5eb","added_by":"auto","created_at":"2026-03-17 07:57:28","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":7867802,"visible":true,"origin":"","legend":"\u003cp\u003eRoot Mean Square Deviation (RMSD) of Ligands in Interaction with Receptors\u003c/p\u003e\n\u003cp\u003e(a)Quercetin/ESR2 (b) Kaempferol/ESR2 (c) Quercetin/HTR2C (d) Kaempferol/SLC6A3 (e) Quercetin/CNR2; (f) Kaempferol/CNR2.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/7841744abddeeca9feb3821a.png"},{"id":104665625,"identity":"171dcda0-5234-45cb-b98f-d1d10d4a37c0","added_by":"auto","created_at":"2026-03-15 15:31:12","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":5964961,"visible":true,"origin":"","legend":"\u003cp\u003eRoot Mean Square Fluctuation (RMSF) of Receptor Proteins in Interaction with Ligands\u003c/p\u003e\n\u003cp\u003e(a) ESR2 with Quercetin; (b) ESR2 with Kaempferol; (c) HTR2C with Quercetin; (d) SLC6A3 with Kaempferol; (e) CNR2 with Quercetin; (f) CNR2 with Kaempferol.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/6f2091af11a5a112db660588.png"},{"id":104782101,"identity":"7752c688-7654-4ebf-9dc0-8a7ec1a27747","added_by":"auto","created_at":"2026-03-17 07:56:50","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":2148946,"visible":true,"origin":"","legend":"\u003cp\u003eRoot Mean Square Fluctuation (RMSF) of Ligand Atoms in Interaction with Receptors\u003c/p\u003e\n\u003cp\u003e(a) Quercetin atoms (ESR2); (b) Kaempferol atoms (ESR2); (c) Quercetin atoms (HTR2C); (d) Kaempferol atoms (SLC6A3); (e) Quercetin atoms (CNR2); (f) Kaempferol atoms (CNR2).\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/dac7090b61ee2567d8141d65.png"},{"id":104665623,"identity":"b04b1585-a438-45e4-bc2f-e3cd93f4e7ea","added_by":"auto","created_at":"2026-03-15 15:31:12","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":4957413,"visible":true,"origin":"","legend":"\u003cp\u003eInteractions and Contacts between Receptors and Ligands\u003c/p\u003e\n\u003cp\u003e(a) ESR2/Quercetin; (b) ESR2/Kaempferol; (c) HTR2C/Quercetin; (d) SLC6A3/Kaempferol; (e) CNR2/Quercetin; (f) CNR2/Kaempferol.\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/7059ebf4b6b8c6267c4b601b.png"},{"id":104665626,"identity":"101528ab-35b0-4b8b-8626-a5207a7ae9b5","added_by":"auto","created_at":"2026-03-15 15:31:12","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":1947532,"visible":true,"origin":"","legend":"\u003cp\u003eNature of Receptor-Ligand Interactions\u003c/p\u003e\n\u003cp\u003e(a) ESR2/Quercetin; (b) ESR2/Kaempferol; (c) HTR2C/Quercetin; (d) SLC6A3/Kaempferol; (e) CNR2/Quercetin; (f) CNR2/Kaempferol.\u003c/p\u003e","description":"","filename":"Figure9.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/c079540b710ed9177e650826.png"},{"id":104782310,"identity":"95ee3df8-6d58-415d-a960-91b6d9dbfddc","added_by":"auto","created_at":"2026-03-17 07:57:08","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":1706878,"visible":true,"origin":"","legend":"\u003cp\u003eDetailed Receptor and Ligand Molecular Interactions\u003c/p\u003e\n\u003cp\u003e(a) ESR2/Quercetin; (b) ESR2/Kaempferol; (c) HTR2C/Quercetin; (d) SLC6A3/Kaempferol; (e) CNR2/Quercetin; (f) CNR2/Kaempferol.\u003c/p\u003e","description":"","filename":"Figure10.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/7212212c75a3c65fee1fa8ac.png"},{"id":104665624,"identity":"50057b12-052b-4d18-aa6f-ce15c4f981b0","added_by":"auto","created_at":"2026-03-15 15:31:12","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":3481386,"visible":true,"origin":"","legend":"\u003cp\u003eTorsion Profiles of Quercetin and Kaempferol across Target Receptors\u003c/p\u003e\n\u003cp\u003e(a) Quercetin/ESR2; (b) Kaempferol/ESR2; (c) Quercetin/HTR2C; (d) Kaempferol/SLC6A3; (e) Quercetin/CNR2; (f) Kaempferol/CNR2.\u003c/p\u003e","description":"","filename":"Figure11.png","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/57eb57992661d9b071c84b19.png"},{"id":104785103,"identity":"05af0ad8-2dc6-486b-9f0a-ad79d1a3d555","added_by":"auto","created_at":"2026-03-17 08:09:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":28944144,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8627630/v1/e1195f3d-1f48-4ca4-8428-0ad044631e7d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Quercetin and Kaempferol as Potential Modulators of Dopaminergic, Serotonergic, and Estrogenic Receptors: Computational Insights into Female Reproductive Health","fulltext":[{"header":"1.0 Introduction","content":"\u003cp\u003ePlant-based natural compounds, have been used extensively to treat various pathological processes due to their superior tolerability and higher bioavailability when compared to synthetic drugs \u003csup\u003e1\u003c/sup\u003e. Flavonoids and non-flavonoids are two significant groups of phenols. Flavonoids, which are frequently present in fruits, vegetables, and herbs, have a variety of therapeutic uses, including antiviral, anti-inflammatory, cytotoxic, antioxidant, cardioprotective, and neuroprotective effects \u003csup\u003e2,3\u003c/sup\u003e. Fruits, vegetables, and herbs are frequently rich in flavonoids, which are chemicals with a variety of therapeutic uses, including antiviral, anti-inflammatory, cytotoxic, antioxidant, cardioprotective, and neuroprotective effects \u003csup\u003e2,3\u003c/sup\u003e. The majority of these flavonoids are related to the steroid sex hormone 17β-estradiol \u003csup\u003e4\u003c/sup\u003e. Thus, phytoestrogenic flavonoids affect gene expression, cellular communication, and physiological responses by interacting with the ER2, SLC6A3, HTR2A and CNR2 and potentially imitating, modifying, or blocking their actions \u003csup\u003e5\u003c/sup\u003e. It has been proposed that a number of phytoestrogens attach to and activate ERα and ERβ \u003csup\u003e6\u003c/sup\u003e. The research on quercetin's impact on ERs, however, has conflicting findings. See Fig. 1 for Kaempferol (KAE) structure \u003csup\u003e7\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eA phytoestrogen with possible health benefits, quercetin is a member of the flavonol subclass of flavonoid chemicals. Many fruits and vegetables contain it, although onions are the main source \u003csup\u003e8\u003c/sup\u003e. Quercetin may have a variety of biological effects, such as antimicrobial, anticancer, antihypertensive, anti-inflammatory, and antioxidant effects, according to a number of in vitro and in vivo investigations \u003csup\u003e9\u003c/sup\u003e. According to some research on quercetin's estrogenic activity, it only has anti-estrogenic effects on the estrogen-sensitive breast cancer cell line MCF-7 \u003csup\u003e10\u003c/sup\u003e. However, other studies have discovered that quercetin has dose-dependent effects that are both estrogenic and anti-estrogenic (Fig. 2) \u003csup\u003e11\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn females, the ovaries and placenta generate the majority of estrogen (Fig. 3), a steroid molecule that has significant modulatory effects on both physiological and pathological processes \u003csup\u003e12\u003c/sup\u003e. According to Çiftci \u003csup\u003e13\u003c/sup\u003e, it affects the development, differentiation, and operation of several target organs, including the reproductive organs of both sexes. While estrogen shortage has been linked to osteoporosis, neurological illnesses, cardiovascular disease, and obesity \u003csup\u003e14,15\u003c/sup\u003e, estrogen is involved in the development of breast, ovarian, endometrial, and prostate cancer \u003csup\u003e16\u003c/sup\u003e. When estrogen binds to the estrogen receptors (ERs), it causes a number of cellular alterations. ERα and ERβ are the two primary types of ERs. According to Klinge et al. \u003csup\u003e17\u003c/sup\u003e, ERs are ligand-dependent transcription factors that facilitate the normal biological activities of estrogens by controlling gene transcription through estrogen response elements (EREs). However, a number of conditions, including different types of cancer and gynecological conditions like polycystic ovary syndrome and endometriosis, can be brought on by aberrant ER signaling \u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eNumerous brain activities depend on dopamine (DA) \u003csup\u003e19,20\u003c/sup\u003e, and it is also linked to inflammation \u003csup\u003e21,22\u003c/sup\u003e, heart failure \u003csup\u003e23,24\u003c/sup\u003e, cancer \u003csup\u003e25,26\u003c/sup\u003e, circadian rhythms, and sleep \u003csup\u003e27,28\u003c/sup\u003e. Given that the human DA transporter protein (hDAT) in the plasma membrane is one of the primary regulators of synaptic DA transmission \u003csup\u003e29\u003c/sup\u003e, genetic variation in the coding gene SLC6A3 in human chromosome 5 (chr5) may impact SLC6A3 function, change the density of hDAT, DA reuptake activity, and the dynamics of DA neurotransmission, all of which can contribute to pathophysiology in the central (CNS) and peripheral nervous systems.\u003c/p\u003e\n\u003cp\u003eThe central nervous system expresses at least 14 different subtypes of serotonin (5-hydroxytryptamine; 5-HT) receptors \u003csup\u003e30\u003c/sup\u003e. Biochemical studies show that pharmacological modulation of the 5-HT2C receptor considerably influences dopamine transmission in the dorsal striatum \u003csup\u003e31\u003c/sup\u003e, despite electrophysiological results supporting a preferential regulation of mesocorticolimbic dopamine pathways by the 5-HT2C receptor subtype \u003csup\u003e32\u003c/sup\u003e. 5-HT2C receptors have been demonstrated to give projection neurons in the basal ganglia's output regions, such as the substantia nigra pars reticulate (SNr) excitatory drive \u003csup\u003e33\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIt is believed that all of the main drugs of abuse, including as opiates and psychomotor stimulants, work by facilitating mesolimbic dopamine transmission. For instance, morphine causes mesolimbic dopamine neurons to be excited mainly by lowering GABAergic inhibition of dopaminergic cells \u003csup\u003e34\u003c/sup\u003e, whereas cocaine increases dopamine availability in the synapse by blocking the transporter mediating dopamine reuptake into the presynaptic terminal \u003csup\u003e35\u003c/sup\u003e. Therefore, it is evident that pharmacological medications that affect dopamine transmission may be able to modify the behavioral and reinforcing effects of drugs of abuse. The 5-HT receptor subtypes that are known to alter mesolimbic dopamine activity, including the 5-HT2C receptor, have received a lot of attention in this context.\u003c/p\u003e\n\u003cp\u003eThe stability and mechanism of binding of quercetin and kaempferol, two flavonols, on the receptors of reproductive importance are poorly understood and to develop more effective and selective medications for this novel possible target, ligand binding mechanisms must be clarified. To fully understand this process, molecular dynamics techniques can offer a powerful research method. Using this method, we can forecast how the phytochemicals from \u003cem\u003eA. garckeana\u003c/em\u003e could interact with significant biological targets linked to the sexual health of women. Therefore, the purpose of this study is to present reliable data about the mode of action and binding stability of quercetin and kaempferol to selected receptors.\u003c/p\u003e"},{"header":"2.0 Materials","content":"\u003cp\u003e \u003cem\u003eHardware and Software Requirements\u003c/em\u003e \u003c/p\u003e \u003cp\u003eDell Latitude 3190 workstation with Intel(R) Pentium(R) Silver N5000 CPU @ 1.10 GHz, Intel(R) UHD Graphics 605 graphics card with hardware stereo, 8 GB RAM, and 120 GB hard drive. Molecular docking was done using the Schr\u0026ouml;dinger Suite.\u003c/p\u003e \u003cp\u003e \u003cem\u003eDatabases and Receptor Structures\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThree-dimensional structures of target hormones and neurotransmitter receptors were obtained using the Protein Data Bank (PDB) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.rcsb.org/\u003c/span\u003e\u003cspan address=\"https://www.rcsb.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Chemical structures and information about the compounds were retrieved using PubChem (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubchem.ncbi.nlm.nih.gov/\u003c/span\u003e\u003cspan address=\"https://pubchem.ncbi.nlm.nih.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Methods\u003c/h2\u003e \u003cp\u003e \u003cem\u003eLigand preparation\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe PubChem database provided the two-dimensional structures of quercetin and kaempferol. According to Brooks et al. \u003csup\u003e36\u003c/sup\u003e, the ligand library was then produced using Ligprep (Schrodinger suite version 2023) and put into a docking program (Maestro).\u003c/p\u003e \u003cp\u003e \u003cem\u003eProtein preparation\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe proteins used in this investigation were sourced from the \"Protein Data Bank.\" Each protein complex in this investigation was prepared using the Protein Preparation workflow (PrepWizard) in Maestro (Maestro, 2023), as explained by Madhavi et al. \u003csup\u003e37\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cem\u003eMolecular Docking\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe Glide module was started in Maestro when the protein and ligand were ready. It was possible to identify the protein's binding location by sampling the ligand's rotatable bonds and torsional degrees of freedom. Glide's Extra Precision (XP) mode was utilized to dock the ligand into the protein's binding site and produce potential binding poses. Induced fit docking software on maestro schrodinger was used for induce fit docking (IFD). As described by Brooks et al. \u003csup\u003e36\u003c/sup\u003e, only the top-ranked poses were used for molecular dynamics.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMolecular Dynamics (Maestro \u0026ndash;Desmond)\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMolecular Dynamics (MD) simulations were performed using the technique described by Anand et al. \u003csup\u003e38\u003c/sup\u003e. For MD setup, the docked ligand-receptor complex from IFD was utilized. To neutralize and solvate the system, counterions and water molecules were added to the simulation box. The force field of choice was determined to be OPLS 4. To observe the molecule's dynamic behavior, the system was simulated for 100 nanoseconds. A simulated interaction diagram was used to assess the generated trajectory files.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePharmacokinetics (PK)\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePharmacokinetic (PK) parameters were analyzed using the Patil et al. \u003csup\u003e39\u003c/sup\u003e approach. The compound's ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics were predicted using Schr\u0026ouml;dinger's QikProp.\u003c/p\u003e \u003c/div\u003e"},{"header":"3.0 Results","content":"\u003cp\u003e\u003cstrong\u003eTop 3 Induced Fit Docking Score of Quercetin and Kaempferol in Receptor Targets\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e presents the Induced Fit Docking Scores of quercetin and kaempferol. Quercetin exhibited strong docking scores with CNR2 (Cannabinoid Receptor 2), with the top three scores ranging from \u0026minus;\u0026thinsp;901.69 to -902.03 kcal/mol, with ESR2 (Estrogen Receptor Beta), within a range of -516.51 to -516.78 kcal/mol. Kaempferol, similarly, demonstrated substantial binding to CNR2, (-898.92 to -899.28 kcal/mol), then ESR2, (-515.94 and \u0026minus;\u0026thinsp;516.48 kcal/mol). The SLC6A3 (Dopamine Transporter) receptor, shows the highest docking score of -1068.37 kcal/mol. Figure 4 shows heat maps of interaction between the ligand and receptor sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRoot Mean Square Deviation (RMSD) Analysis of Quercetin and Kaempferol in Complex with Receptors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Root Mean Square Deviation (RMSD) was analyzed for both quercetin and kaempferol in complex with receptors. Some minor deviations were observed at the early stage of simulations. However, both quercetin and kaempferol had RMSD values for the protein and ligands with fluctuations within the range of 1\u0026ndash;3 \u0026Aring;. The RMSD values for both the protein and ligand stabilized at 50ns in ESR2-Quercetin complex and 20ns in ESR2- Kaempferol complex, 70ns in HTR2C-Quercetin complex, 0ns in SLC6A3-Kaempferol complex, 20ns in CNR2-Kaempferol complex while CNR2-Quercetin complex does not reach equilibrium (Fig.\u0026nbsp;5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRoot Mean Square Fluctuation (RMSF) Analysis of Quercetin and Kaempferol in Complex with Receptors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProtein RMSF plot revealed that the N-terminal and C-terminal loops, exhibited higher fluctuation. In contrast, secondary structure elements such as alpha-helices (highlighted with a red background) and beta-strands (highlighted with a blue background) showed lower RMSF values. The loop regions exhibited moderate RMSF values, showing fluctuation not as significant as the N- and C-terminal regions. The protein residues interacting with the ligand were identified and marked with green-colored vertical bars on the RMSF plot. These residues showed lower RMSF values compared to the non-interacting residues. This observation was consistent for both quercetin and kaempferol. (Fig. 6).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTop 3 Induced Fit Docking Score of Quercetin and Kaempferol in Receptor Targets\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eS/N\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTarget\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePhytochemicals\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInduced Fit Docking Score (kcal/mol)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eS/N\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTarget\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePhytochemicals\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInduced Fit Docking Score (kcal/mol)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003eESR2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-516.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"6\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003eCNR2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-902.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-516.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-901.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-516.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-901.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-516.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-899.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-515.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-898.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-515.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-898.92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eSLC6A3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1068.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"3\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eHTR2C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-790.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1068.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-790.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1067.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-790.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eProtein\u0026ndash;Ligand Interaction Timeline, Protein\u0026ndash;Ligand Interaction Profiles and Ligand\u0026ndash;Protein Contacts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe timeline depicts hydrogen bonds, hydrophobic contacts, ionic interactions, and water bridges. (Figs. 7 and 8). Hydrogen bonds (H-bonds) were observed consistently across several complexes, with backbone and side-chain atoms from both protein and ligand participating. Hydrophobic contacts, including \u0026pi;\u0026ndash;cation and \u0026pi;\u0026ndash;\u0026pi; interactions, were frequently observed, especially in complexes involving aromatic or aliphatic moieties on the ligand. These contacts were primarily maintained with nonpolar side chains of residues located in the hydrophobic core of the receptor binding sites. Ionic interactions, which are common in some systems including charged residues such as Asp, Glu, Lys, and Arg, were absent. Water bridges provided extra stability to the complexes by acting as mediators in indirect hydrogen bonding (Fig. 9). Protein-ligand contact analysis demonstrated that quercetin maintained stable connections with critical residues in the ESR2 binding pocket throughout the simulation. Notably, GLU 305 exhibited consistent charged (negative) interactions for 73% and 76% of the simulation time. A polar interaction was also maintained with HIS 475 for 63% of the trajectory, while hydrophobic contact with PHE 356 occurred in 38% of the frames. For Kaempferol, HIS 475 showed a polar interaction involving a water bridge in 78% of the simulation, and GLU 305 sustained a water-mediated charged (negative) interaction in 77% of the frames. Additionally, PHE 356 contributed hydrophobic contacts in 61% of the trajectory via direct interaction and 57% through water mediation (Figs. 10 and 11).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePharmacokinetics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn comparison to quercetin (18.199, score of 2 and 51.649%, 6.511, -5.544 respectively), kaempferol demonstrated significantly higher Caco-2 cell permeability (51.24), human intestinal absorption (3), predicted percentage of oral bioavailability (63.637%), MDCK cell permeability (19.934), and better skin permeability in QPlogKp value (-4.641). Compared to quercetin (5), kaempferol (4) has a significantly smaller number of rotatable bonds.\u003c/p\u003e\n\u003cp\u003eCompared to quercetin (-0.343), kaempferol showed a greater projected plasma protein binding (QPlogKhsa: -0.191) in the distribution profile. Both compounds had low blood-brain barrier permeability (QPlogBB) (-1.893 vs. -2.419), and their CNS scores indicated that they were expected to be inactive. In comparison to 302.24 g/mol, kaempferol had a lower molecular weight (286.24 g/mol) and a smaller molecular volume (844.89 vs. 867.28). The polarity of quercetin is greater (4.721 vs. 4.456).\u003c/p\u003e\n\u003cp\u003eWith minor differences in electrical and structural characteristics, quercetin and kaempferol had metabolic profiles that were mostly similar. The surface area to electron density ratio (dip257; 0.0235) of quercetin was somewhat greater than that of kaempferol. Kaempferol\u0026apos;s ionization potential (IP) is 9.009 eV, while quercetin\u0026apos;s is 8.984 eV. Compared to kaempferol (0.57 eV), quercetin had a slightly higher electron affinity (EA) of 0.623 eV. Kaempferol was expected to produce four metabolic products, whereas quercetin was expected to produce five.\u003c/p\u003e\n\u003cp\u003eBoth compounds had very good profiles in terms of toxicity, excretion, and overall drug-likeness. Neither compound violated Lipinski\u0026apos;s or Jorgensen\u0026apos;s criteria, nor did they show any reactive functional groups. The properties of both compounds were within the recommended physicochemical space (#stars\u0026thinsp;=\u0026thinsp;0). Quercetin (-5.109) and kaempferol (-5.201) both showed low and comparable predicted inhibition of the hERG potassium channel. Kaempferol had a higher human clearance (measured by QPlogPo/w) than quercetin (0.367) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eEvaluation of ADMET Parameters for Quercetin and Kaempferol\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eS/N\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQuercetin\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKaempferol\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCaco-2 Permeability (QPPCaco)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.199\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHIA (HumanOralAbsorption)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOral Bioavailability (% Human Oral Absorption)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51.649\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63.637\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of rotatable bonds (#rotor)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSolvent-accessible surface area (SASA)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e519.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e507.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMDCK cell permeability (QPPMDCK)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.511\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.934\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSkin permeability (QPlogKp)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-4.641\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePredicted oral absorption (HumanOralAbsorption)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlasma Protein Binding (QPlogKhsa)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.343\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.191\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBBBP Probability (QPlogBB)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.419\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCNS activity (CNS)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMolecular weight (mol MW)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e302.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e286.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipole moment (dipole)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.721\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.456\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMolecular volume (volume-1)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e867.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e844.89\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePredicted binding to serum albumin (QPlogKhsa)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.343\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.191\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurface Area / Electron density (dip^2/V)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0257\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0235\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIonization potential (IP eV)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.984\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElectron affinity (EA eV)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of predicted metabolic products (#metab)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehERG Inhibition (QPlogHERG)\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.201\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePredicted blocking of hERG channels\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.201\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of reactive functional groups\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (rtvFG)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLipinski Rule Violations\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJorgensen Rule Violations\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProperties outside recommended range\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (#stars)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (#stars)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHuman Clearance (QPlogPo/w)\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.367\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlockage of hERG K\u0026thinsp;+\u0026thinsp;channels\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.201\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"4. 0 Discussion","content":"\u003cp\u003ePlants, fruits, vegetables, and leaves naturally contain phenolic molecules called flavonoids, which are phytochemicals with a variety of therapeutic uses, including antiviral, anticancer, antioxidant, anti-inflammatory, neuroprotective, cardioprotective, and aphrodisiac qualities \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. According to earlier network pharmacology and molecular docking studies, estrogen receptor beta plays a significant role in improving the sexual health of women.\u003c/p\u003e \u003cp\u003eInduced Fit docking studies gave stronger proof of how well these plant compounds binds to their intended targets in the body. It is particularly intriguing to see how incredibly strongly quercetin and kaempferol bind to SLC6A3, which modifies dopamine availability in the brain \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Both Quercetin and Kaempferol binds tightly to the CNR2 which are extremely significant because estrogen receptor beta and cannabinoid receptor 2 are known to be essential for sexual behavior and reward perception. Strong binding of Quercetin with HTR2C receptor may exerts both tonic and phasic modulation of central dopamine transmission via activation of 5-HT2C receptors as several lines of evidence has indicated. Both Quercetin and Kaempferol showed a strong binding (although the least of all) with ESR2. This also suggests that Quercetin could act like phytoestrogens, mimicking or adjusting the effects of our body's natural estrogen. Ruan et al. \u003csup\u003e42\u003c/sup\u003e reported kaempferol as an effective modulator in endometrial cancer treatment.\u003c/p\u003e \u003cp\u003eValues of RMSD of quercetin, kaempferol and that of the receptor were fairly constant between 1-3A except CNR2-Quercetin complex which failed to stabilize. It means that the protein structures with Quercetin and Kaempferol generally remained stable throughout the simulation and stabilized. RMSF demonstrates weather the receptor-protein residues are flexibility, providing information about the local movements and change of some region within the protein chain \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. The C-terminal and N-terminal loops were more volatile, which is typical in protein dynamics. Secondary structure elements with lower RMSF such as beta-strands and alpha-helices, however, were not fluctuating and were more rigid. The helices and strands like most components of secondary structure did not show signs of breaking apart during the simulation. Throughout the simulation courses, some patterns of contact are traced by the depiction of the interaction of proteins and ligands \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn complexes involving aromatic or aliphatic moieties on the ligand, hydrophobic contacts, such as π\u0026ndash;cation and π\u0026ndash;π interactions, were commonly observed. Nonpolar side chains of residues found in the hydrophobic core of the receptor binding sites were mostly responsible for maintaining these interactions. Water molecules acted as mediators in indirect hydrogen bonding to create water bridges, which gave the complexes more stability.\u003c/p\u003e \u003cp\u003eQuercetin formed consistent bonds with important residues in ESR2, HTR2C, SLC6A3 and CNR2 binding pocket. For over 70% the simulation period, respectively, Hydrophobic interactions with PHE, LEU, TRP were very instrumental in ensuring the stability of the complex. GLU, ASP demonstrated continuous charged (negative) interactions, suggesting robust and potentially dual connections, both water-mediated and direct. For over 70% of the trajectory, a polar association was also maintained with HIS, SER, THR. These results point to a polar and charged interaction-dominated, somewhat constant, and unique interaction profile between quercetin and ESR2. In comparison to quercetin, the greater frequency and diversity of interactions seen with kaempferol point to a stronger and possibly more adaptable binding profile. The impact of these interactions was also found by Lotfi et al. \u003csup\u003e45\u003c/sup\u003e, indicating that natural flavonoids may have therapeutic potential for treating osteoporosis by targeting ERs.\u003c/p\u003e \u003cp\u003eKaempferol showed exceptional qualities in terms of absorption across the majority of assessed criteria. It showed noticeably increased Caco-2 cell permeability, suggesting improved intestinal absorption potential, improved intestinal absorption in humans and a higher estimated oral bioavailability percentage (63.637%). Kaempferol has a smaller number of rotatable bonds suggesting a stiffer structure that would promote permeability. Additionally, kaempferol showed improved skin permeability and increased MDCK cell permeability, superior oral absorption profile and distribution profile. Although both flavonol were expected to be inactive in the central nervous system, kaempferol had a significantly less negative value, indicating somewhat higher CNS penetration, despite the fact that both compounds had poor blood-brain barrier permeability. Furthermore, Kaempferol possessed two advantageous characteristics for distribution: a lower molecular weight and a smaller molecular volume. This is consistent with other research that has been done on the bioactivity, therapeutic potential, and bioavailability of quercetin and kaempferol \u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWith minor differences in electrical and structural characteristics, quercetin and kaempferol had metabolic profiles that were mostly similar. Similar tendencies to lose electrons were indicated by the nearly identical ionization potential (IP) values. Similarly, quercetin's electron affinity (EA) was marginally higher than kaempferol's, indicating a marginally higher capacity to take up electrons. Quercetin was expected to produce five metabolic products in terms of metabolic stability, while Kaempferol produced four, suggesting that Quercetin may have a little higher metabolic complexity. Oliveira et al. \u003csup\u003e48\u003c/sup\u003e used LC-ESI MS to examine the metabolism of quercetin and kaempferol by rat hepatocytes. They discovered that both flavonoids were extensively metabolized (98.8 +/- 0.1% and 81.0 +/- 5.1%, respectively, n\u0026thinsp;=\u0026thinsp;4), with two kaempferol glucuronides and four quercetin glucuronides detected after incubation. Both compound obeyed Lipinski's and Jorgensen's rules and neither displayed any reactive functional groups, highlighting their adherence to accepted drug-likeness standards. Furthermore, neither molecule exhibited any characteristics outside of the suggested physicochemical area (#stars\u0026thinsp;=\u0026thinsp;0). Both quercetin and kaempferol showed modest and comparable predicted blockage of the hERG potassium channel, a crucial indicator of cardiotoxicity, indicating a minimal risk of hERG-mediated deleterious cardiac consequences. Compared to quercetin, kaempferol had a greater human clearance (measured by QPlogPo/w), suggesting a possible quicker rate of excretion or metabolic turnover.\u003c/p\u003e \u003cp\u003eAli et al. \u003csup\u003e49\u003c/sup\u003e used pharmacokinetic and docking software to examine the druggability and binding affinities of quercetin and kaempferol towards a number of antidiabetic targets in order to study the multi-targeting antidiabetic potential of these drugs. Both quercetin and kaempferol have favorable ADMET profiles, low predicted cardiotoxicity (low hERG inhibition), and conform to Lipinski's and Jorgensen's rules.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates that the flavonoids quercetin and kaempferol exhibit strong multi-target binding affinities toward key receptors implicated in female sexual health, including ESR2, HTR2C, SLC6A3, and CNR2. Molecular docking and dynamic simulations confirmed stable receptor\u0026ndash;ligand interactions dominated by hydrophobic, polar, and charged contacts. ADMET and drug-likeness analyses revealed favorable pharmacokinetic profiles, with kaempferol showing superior absorption and distribution characteristics. Both compounds complied with established safety and drug-likeness rules, exhibiting low cardiotoxic risk. These findings support the therapeutic potential of quercetin and kaempferol as promising phytoestrogenic candidates for sexual health modulation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInvestigation, methodology, data curation, writing—original draft preparation, M.R.A., A.O.E, and M.B.F; validation, visualisation, resources, software, Z.O.B., M.A.D. and K.O.S.; conceptualisation, writing—review and editing, M.A.A and Q.O.N. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors appreciate the contribution of Mr. Dele Aiyepeku of the Department of Biochemistry, University of Ilorin, Ilorin, Nigeria, for the technical assistance provided in the course of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMuhammed Robiu Asinmi, ORCID: https://orcid.org/0000-0003-4886-4687\u003c/p\u003e\n\u003cp\u003eAbdulAzeez Olamilekan Elemosho \u0026nbsp;\u0026nbsp;ORCID: https://orcid.org/0000-0001-6480-7995\u003c/p\u003e\n\u003cp\u003eMansurat Bolanle Falana, ORCID: https://orcid.org/0000-0003-4370-3059\u003c/p\u003e\n\u003cp\u003eZainab Olajumoke Bello\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;ORCID: https://orcid.org/0000-0002-9790-0472\u003c/p\u003e\n\u003cp\u003eMuhammad Ali DikwaORCID: https://orcid.org/0009-0002-7819-6683\u003c/p\u003e\n\u003cp\u003eKamaldeen Olalekan Sanusi \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; ORCID: https://orcid.org/0000-0002-9588-7710\u003c/p\u003e\n\u003cp\u003eMusbau Adewumi Akanji \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;ORCID: https://orcid.org/0000-0003-4476-454X\u003c/p\u003e\n\u003cp\u003eQuadri Olaide Nurudeen \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;ORCID: https://orcid.org/0000-0001-5261-8679\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePatel, S., Chopra, S., Chaurasia, S., and Sarwat, M. 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Pharmaceuticals \u003cem\u003e17\u003c/em\u003e, 757.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ADMET, Kaempferol, Molecular Dynamics, Phamacokinetics, Quercetin","lastPublishedDoi":"10.21203/rs.3.rs-8627630/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8627630/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNatural polyphenols like kaempferol and quercetin draws interest because of their ability to interact with multiple receptors. This study determines the pharmacokinetic characteristics, stability, and binding dynamics of quercetin and kaempferol.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eProtein and ligand structures were obtained from the Protein Data Bank and PubChem, respectively. LigPrep and Protein Preparation Wizard (Schr\u0026ouml;dinger Suite 2023) were used to prepare the ligands and protein, respectively. Docked complexes were prepared subjected to 100 ns MD simulations using Desmond. Both ligands formed stable complexes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWith variations within 1\u0026ndash;3 \u0026Aring; range, the RMSD values for quercetin and kaempferol stabilized at about 50ns, and some earlier. RMSF plots demonstrated consistent interactions with important residues and decreased mobility in ligand-binding areas. Throughout the simulation, PHE, LEU and TRP formed persistent hydrophobic interactions, HIS, SER, THR and ASN formed polar interactions stable hydrogen bonds while GLU and ASP contributes negatively charged interactions. Both kaempferol and quercetin shows excellent metabolic stability and drug-likeness. Kaempferol, shows better ADMET properties and interaction consistency.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eDue to the presence of stable and prolonged activation of ESR2, HTR2C and SLC6A3 the therapeutic value of kaempferol and quercetin in enhancing the sexual health of women is confirmed, with kaempferol showing better profile.\u003c/p\u003e","manuscriptTitle":"Quercetin and Kaempferol as Potential Modulators of Dopaminergic, Serotonergic, and Estrogenic Receptors: Computational Insights into Female Reproductive Health","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-15 15:31:07","doi":"10.21203/rs.3.rs-8627630/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-03T08:52:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215135060856629635861695161454713401408","date":"2026-03-24T01:10:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-10T15:50:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-19T15:53:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-19T09:14:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-19T09:12:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pharmacology and Toxicology","date":"2026-01-17T17:27:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a0e1267e-c9aa-49a4-b957-7e97ae96ec2f","owner":[],"postedDate":"March 15th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-15T15:31:07+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-15 15:31:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8627630","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8627630","identity":"rs-8627630","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}