Targeting Age-Associated NAD⁺ Decline: in silico Evaluation of Minocycline as an Inhibitor of CD38 and PARP2

Targeting Age-Associated NAD⁺ Decline: in silico Evaluation of Minocycline as an Inhibitor of CD38 and PARP2 | 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 Targeting Age-Associated NAD⁺ Decline: in silico Evaluation of Minocycline as an Inhibitor of CD38 and PARP2 Oluwasegun Davis Olatomide, Sunday Abraham Musa, Zainab Mahmood Bauchi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7474241/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Chronic activation of enzymes that require NAD⁺ for their activity such as CD38 and PARPs accelerates its decline with age, impairing cellular metabolism and contributing to degenerative processes. Targeting these enzymes may help preserve NAD⁺ levels and delay ageing-related pathologies. This study investigated the potential inhibitory activity of minocycline against CD38 and PARP2 using in silico approaches. Structures of minocycline and standard inhibitors for CD38 and PARPs were obtained from PubChem, while protein structures were retrieved from the Protein Data Bank (PDB). The ligands were docked against the protein using PyRx, and ligand-protein interactions were visualized with Discovery Studio Visualizer. Pharmacokinetic properties were assessed via pkCSM, toxicity was predicted using ProTox, and membrane permeability evaluated using PerMM. Ligands with favourable docking scores were further subjected to molecular dynamics (MD) simulations over a 100 ns trajectory. Minocycline demonstrated higher binding affinity for CD38 (− 8.9 kcal/mol) and PARP2 (− 10.2 kcal/mol) compared to their respective standard inhibitors (− 8.4 and − 10.1 kcal/mol). MD simulations revealed that minocycline formed more stable complexes with both targets, as indicated by lower root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values. Radius of gyration analysis confirmed compact and stable protein-ligand complexes. These results suggest that minocycline may inhibit NAD⁺ consumers more effectively than existing inhibitors, potentially preserving NAD⁺ levels and mitigating the ageing process. The findings support the rationale for repurposing minocycline as a multi-target anti-ageing therapeutic. Computational Biology Drug Discovery, Design, & Development Minocycline CD38 PARP2 drug repurposing ageing NAD⁺ consumers Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 1.0 Introduction DNA damage and genomic instability have been considered as major driving forces of rapid ageing (McKinnon, 2017 ). It is estimated that above 10,000 DNA lesions accumulate in each cell daily (Milano et al., 2024 ). Accumulation of these lesions are caused by consistent exposure to endogenous agents, “including reactive nitrogen species (RNS), reactive oxygen species (ROS)”, and environmental sources, like carcinogens, radiation and chemical mutagens (Fakouri et al., 2019 ; Carusillo & Mussolino, 2020 ). Hence, to maintain the normal function of the cell, repair in nucleotide, bases, single strand break and double strand breaks occur in cell (Chatterjee & Walker, 2017 ; Polyzos et al., 2024 ). Decline in the ability of the cell to repair DNA lesions occur as we age leading to its accumulation and blockage of DNA replication forks thus inhibiting cell cycle progression in proliferating cells (Yousefzadeh et al., 2021 ; Herr et al., 2024 ). Just like the repair proteins, recruitment proteins are also important in response to DNA damage (Waters & Spratt, 2024 ). When DNA damage occurs, it activates poly(ADP-ribose) polymerases (PARPs), which utilize NAD⁺ to add ADP-ribose chains to DNA and nearby proteins. This modification acts as an early signal to attract and assemble DNA repair proteins at the site of damage (Bai, 2015 ; Braidy et al., 2019 ; Demarest et al., 2019 ). As organisms age, impairments in DNA repair mechanisms allow damage to accumulate, resulting in prolonged activation of PARPs. This persistent activity consumes NAD⁺ (Johnson & Imai, 2018 ; Demarest et al., 2019 ), a vital molecule required for DNA repair, mitophagy, sirtuin function, mitochondrial maintenance, and several key energy metabolism processes (Fang et al., 2017 ; Johnson & Imai, 2018 ) thus inducing cellular senescence and inflammation which exacerbates age-related diseases (Poljsak & Milisav, 2016 ). During inflammatory response, CD38 which is predominantly expressed on immune cells is activated (Chini et al., 2024 ). The ageing process is associated with prolonged periods of inflammation which leads to increased CD38 activation, leading to a marked reduction in NAD⁺ levels within the cells, thus, reducing its activity (Hogan et al., 2019 ). Targeting the biological processes of ageing, with the aim of promoting a longer period of healthy life are currently of interest (Schinaman et al., 2019 ). This is based upon the hypothesis that by slowing the ageing process itself, it may be possible to delay the occurrence and progression of chronic, age-related diseases (Kaeberlein et al., 2015 ). Reports from several studies have shown that increasing the cellular levels of NAD⁺ has the potential to reduce the effects of ageing and delay the onset of age-related disorders (Houtkooper et al., 2010 ; Trammell et al., 2016 ). Increasing NAD⁺ levels—through intake of NAD + precursors and interventions like aerobic exercise, caloric restriction, and fasting—has been shown to extend lifespan in animal models (Zhang et al., 2016 ; Yoshino et al., 2018 ; Burtscher et al., 2024 ). Inhibitors of PARPs and CD38 activity are currently showing promise against several degenerative diseases like cancer, Diabetes, cardiovascular disease and ageing (Tarragó et al., 2018 ; Li et al., 2024 ). Hence there is a need to identify anti-ageing compounds with multifaceted inhibitory effect on these NAD + consumers. Minocycline, formally known as 7-dimethylamino-6-desoxytetracycline, belongs to the second-generation tetracycline family and is an FDA-approved antibiotic (Yang et al., 2020 ). It has been in use for more than three decades to combat, both Gram-positive and Gram-negative (Yun et al., 2017 ). Minocycline has emerged as a promising therapeutic agent for neurological disorders, owing to its ability to penetrate the blood–brain barrier. Experimental studies in animal models have consistently shown that it attenuates neuroinflammation and mitigates neuronal loss in several neurodegenerative diseases (Yun et al., 2017 ; Yang et al., 2020 ). Although some studies suggest that minocycline treatment in Drosophila enhances FOXO activity—a transcription factor downstream of insulin/TOR signaling and known to regulate stress responses and longevity across species—important questions still remain (Lee et al., 2017 ; Lim & Hyun, 2022 ). Minocycline’s ability to extend lifespan in the w 1118 Drosophila strain, with impaired tryptophan transport (Lee et al., 2017 ),— does not support the previously proposed hypothesis that its pro-longevity effects are mediated through the kynurenine pathway (Oxenkrug et al., 2012 ). However, it is possible that the minocycline-induced extension of lifespan in the w 1118 strain was through its supplementation of NAD + or through its ability to prevent depletion of NAD + with age. NAD⁺ is produced through multiple biosynthetic routes, including the Preiss–Handler, salvage, and de novo pathways. In the de novo pathway, tryptophan is metabolized through the kynurenine pathway, ultimately generating NAD⁺ via the intermediate compound quinolinic acid (QA) (Cambronne & Kraus, 2020 ). This implies that the lifespan extension seen in the w 1118 strain, which has impaired intracellular tryptophan transport, could be due to the ability of minocycline to supplement levels of NAD + through the salvage pathway or its ability to inhibit NAD-consuming enzymes. However, this hypothesis remains to be tested. Computational biology and bioinformatics offer efficient and cost-effective approaches for identifying and optimizing potential lead compounds (Onyango et al., 2022 ). Hence, the present study screened minocycline and potent inhibitors against CD38 and PARP 2. 2.0 Materials and Methods 2.1 Materials Most computational analyses were conducted on a system equipped with an Intel® Pentium® CPU B970 @ 2.30 GHz and 4 GB RAM, utilizing a range of software tools including PyMOL, PyRx, Discovery Studio, and Desmond. Additionally, various online databases and web servers—such as PubChem, pkCSM, ProTox3, CASTp, PerMM, PASS, KEGG, and the Protein Data Bank (PDB)—were employed for compound sourcing, prediction, and molecular analysis. 2.1.1 Retrieval of the ligands Three-dimensional structures of minocycline (CID: 54675783), CD38 inhibitor 78c (CID: 118736856), and niraparib (CID: 24958200), which serve as standard inhibitors for CD38 and PARP2, were retrieved in Structure Data File (SDF) format from “the PubChem database ( https://pubchem.ncbi.nlm.nih.gov/ )” (Marisa et al., 2021 ) (Table 1 ). 2.1.2 Retrieval of proteins The 3D crystal structure of cyclic ADP ribose hydrolase (CD38) in complex with with a novel CD38-targeting antibody SAR650984 (PDB ID: 4CMH) with resolution of 1.53 Å, and poly(ADP-ribosyl)transferase-like 2 protein (PARP2) in complex inhibitor STO1542 (PDB ID: 4L7N) with 1.80 Å were downloaded from the “RCSB protein data bank ( https://www.rcsb.org/ )” (Table 2 ). 2.2 ADMET and Druglikeness The ADMET and drug-likeness profiles of minocycline, CD38 inhibitor 78c, and niraparib were evaluated using the "pkCSM web server ( http://biosig.unimelb.edu.au/pkcsm/prediction)”(Marisa et al., 2021) . This tool predicts key pharmacokinetic parameters—including Absorption, Distribution, Metabolism, Excretion, and Toxicity—based on structural input. Lipinski’s Rule of Five was applied to assess drug-likeness (Chandel et al., 2022 ). Additional pharmacokinetic predictions included Caco-2 cell permeability, “intestinal absorption, skin permeability, volume of distribution (VDss), blood–brain barrier and CNS permeability, cytochrome P450 inhibition profiles, total clearance, and hepatotoxicity” (Kumari & Dalal, 2022 ). Parameters such as Caco-2 and skin permeability, along with P-glycoprotein interaction, were specifically used to assess drug absorption potential (Sivani et al., 2021 ). Metabolic profiling was based on cytochrome P450 (CYP) models to assess whether the compounds act as substrates or inhibitors of major CYP isoforms. Excretion parameters were estimated using total clearance values and renal OCT2 substrate prediction. Toxicological assessments included AMES mutagenicity, hERG channel inhibition, hepatotoxicity, and skin sensitization potential (Wahono et al., 2024 ). Toxicity was also predicted by evaluating the carcinogenic, respiratory, nephrotoxic, cardiotoxic, neurotoxic, mutagenic, and cytotoxic effects of the drugs using “ProTox3 ( https://tox.charite.de/protox3/ )” (Banerjee et al., 2024 ). Using the smiles of the compounds derived from the PubChem database, these parameters were calculated and compared against standard ranges (Quirós et al., 2018 ). 2.3 Membrane Permeability The membrane permeability of minocycline, the CD38 inhibitor 78c, and niraparib was evaluated using the “PerMM online tool ( https://permm.phar.umich.edu/permm_server_cgopm)”(Wahono et al., 2024) , which predicts permeability coefficients, quantifies and aids the visualization of the translocation of compounds across lipid bilayer (Lomize et al., 2019 ). Depiction of translocation of the compounds was done using PyMOL ( https://pymol.org/2/ ). 2.4 Preparation of Ligands and Protein The 3D molecular structures of minocycline, CD38 inhibitor 78c, and niraparib were optimized through “energy minimization using the Universal Force Field (UFF) and the conjugate gradient algorithm”, executed over 200 iterations within PyRx-Python Prescription version 0.8 (Broni et al., 2021 ). Post-minimization, structures were converted to the pdbqt format using Open Babel (v2.3.1), incorporating the addition of hydrogen atoms, assignment of partial charges, and definition of rotatable bonds ( https://openbabel.org/wiki/Main_Page ) (Ogunyemi et al., 2022 ). Protein targets were “prepared using BIOVIA Discovery Studio Visualizer 2021 (v21.1) ( https://discover.3ds.com/discovery-studio-visualizer-download )”. During preparation, water molecules and non-essential heteroatoms were removed (Ravindranath et al., 2022 ). Polar hydrogens were added, and co-crystallized inhibitors were removed after identifying the active site. The final protein structures were saved in pdb format for molecular docking (Onyango et al., 2022 ). 2.5 Binding Sites Prediction "The Computed Atlas of Surface Topography of Proteins (CASTp) server ( http://sts.bioe.uic.edu/castp/calculation.html )” (Tian et al., 2018 ) was utilized to identify and evaluate the potential binding pocket of the CD38 protein, which lacked a co-crystallized ligand in its binding site (Bhat et al., 2023 ). For PARP2, the binding site was determined using site map generation in “BIOVIA Discovery Studio Visualizer 2021 (v21.1) ( https://discover.3ds.com/discovery-studio-visualizer-download )”, guided by the position of the co-crystallized ligand (Ruswanto et al., 2022 ). 2.6 Molecular Docking Upon confirmation of favorable ADMET profiles, the prepared ligands were subjected to molecular docking with their respective target proteins using AutoDock Vina, integrated within the PyRx software. The target proteins were converted into pdbqt format, and docking grid boxes were defined based on the predicted binding sites (Onyango et al., 2022 ). For CD38, the grid box was centered at coordinates (24.6352, -19.1628, -13.1669), with dimensions (x = 32.4267, y = 32.5187, z = 30.9969 Å). For PARP2, the grid center was set at (21.1174, -3.5739, 12.4086), with dimensions (x = 30.0298, y = 21.1835, z = 23.6906 Å). The exhaustiveness parameter was increased to 8 to allow for broader conformational sampling. Docking results were assessed based on binding affinity scores, expressed in kcal/mol, where more negative values indicate stronger binding (Azmal et al., 2024 ). The top-scoring conformations were saved in pdb format, and protein–ligand interactions were analyzed using “BIOVIA Discovery Studio Client 2021 (v21.1) ( https://discover.3ds.com/discovery-studio-visualizer-download )” (Ruswanto et al., 2022 ). 2.7 Visualization of Result BIOVIA Discovery Studio Client 2021 (v21.1) was used to examine the interaction profiles (2D and 3D) of the ligand–protein complexes (Liu et al., 2022 ). This analysis focused on identifying critical binding features such as “hydrogen bonding, hydrophobic interactions, and other non-covalent forces to better understand the binding conformation and evaluate the interaction strength” between each ligand and its respective protein target (Azmal et al., 2024 ). The output files, output.pdbqt, and macromolecule, were opened “Biovia Discovery Studio Visualizer 2021 (v21.1) ( https://discover.3ds.com/discovery-studio-visualizer-download )”. During the docking process, only conformations with a RMSD of zero were considered, as these represent the most optimal binding poses (Azmal et al., 2024 ). The binding affinities of minocycline were compared to those of the standard inhibitors for CD38 and PARP2. The top-ranked conformations, based on binding energy and interaction profile, were selected for subsequent molecular dynamics simulation. 2.8 Structure–function Relationships (MD simulation) Molecular dynamics (MD) simulation is used in the exploration of the relationships between structure and function of macromolecules (Wahono et al., 2024 ). The “Protein Preparation Wizard and Prime module in the Schrödinger Suite” was used to prepare the selected protein–ligand complexes before MD simulation (Kumar et al., 2020 ). The steric clashes and strained geometries within the complexes were fixed through “restrained energy minimization, which allowed movement of heavy atoms up to 0.3 Å”. To evaluate the stability and dynamic behavior of the complexes, a 100-nanosecond molecular dynamics (MD) simulation was conducted using Desmond (Schrödinger, 2021 ; Chandel et al., 2022 ). The complexes were optimized using standard fixed-charged force fields and solvation in transferable intermolecular potential with three points (TIP3P) water model and 0.15 M NaCl. Afterwards, energy minimization for 100 picoseconds (ps) was done prior to the run. MD simulation was then carried out at a temperature (300 K) using the NPT ensemble in an orthorhombic simulation box, with buffer dimensions of 10 × 10 × 10 ų. System energy (kcal/mol) was recorded at 1.2 picoseconds intervals throughout the simulation To ensure electrostatic neutrality, Na⁺ or Cl⁻ counterions were added to balance the net charge of the protein–ligand complex (Chandel et al., 2022 ). The stability and conformational dynamics of the simulated complexes were determined by assessing the RMSD, RMSF, solvent-accessible surface area (SASA), and radius of gyration (Rg) (Azmal et al., 2024 ). 2.9 Potential Bioactivity Profiles To evaluate the potential bioactivity of minocycline and the standard inhibitors, the “Prediction of Activity Spectra for Substances (PASS) online server ( https://www.way2drug.com/passonline/predict.php )” (Alfarado et al. ). Through the generation of two parameters: “the probability of activity (Pa) and the probability of inactivity (Pi)”, this tool estimates the potential pharmacological effects of test compounds (Maity et al., 2025 ). This was done to further buttress the observations seen in literatures. 2.10 Analysis of Metabolic Pathway “Metabolic pathway analysis was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database ( https://www.genome.jp/kegg/pathway.html )” (Azmal et al., 2024 ). 2.11 Protein-protein interaction network analysis The “STRING database ( https://string-db.org/ ) was used to determine protein–protein interaction (PPI)” (Zhou et al., 2025 ) for CD38 and PARP2. The resulting PPI networks offer valuable insights into potential interacting protein residues that may modulate or be affected by inhibition of the target proteins (Azmal et al., 2024 ). 3.0 Results 3.1 ADMET and druglikeness studies Minocycline and the standard inhibitors passed the rule of five (RoF) parameter with only minocycline failing the assumption of TPSA with TPSA > 140, hence, depicting high druglikeness (Fig. 1A). Minocycline and the standard inhibitors all showed good to very good water solubility with values ranging from (<-2 to <-4). The result also revealed between moderate and high CaCo-2 permeability and intestinal absorption with minocycline having the least absorption in comparison with the standard inhibitors. With regard to skin permeability, minocycline and the standard inhibitors showed a constant skin permeability value of > 2.740. They were substrates of P-Glycoprotein. CD38 inhibitor 78c was predicted to be a P-glycoprotein I inhibitor while Niraparib was predicted to inhibit both P-glycoprotein I and P-glycoprotein II. We also observed a moderate (minocycline) to very high (standard inhibitors) distribution volume for all the compounds. For blood–brain barrier membrane permeability, a logBB >-1 but < 0.3 in this study suggests that minocycline and the standard inhibitors poorly crossed the blood–brain barrier. For CNS permeability minocycline and the standard inhibitors were predicted to poorly penetrate the CNS since (logPS <-2). minocycline and the standard inhibitors are not substrate of CYP2D6, but, CD38 inhibitor 78c and Niraparib are substrate of CYP3A4. Minocycline is not an inhibitor of any CYPs, however, CD38 inhibitor 78c inhibits CYP1A2, CYP2C19, CYP2C9 and CYP3A4 while Niraparib inhibits CYP1A2 and CYP2D6. They all showed high clearance value (Table 3 ). The results also suggest that minocycline and the standard inhibitors are not toxic in AMES test, however, CD38 inhibitor 78c and Niraparib are predicted to be hepatotoxic and neurotoxic. All compounds were predicted to cause respiratory toxicity, and only niraparib is predicted to have moderate carcinogenic risk (Fig. 1B). Table 3 Computationally predicted values for Minocycline and the standard inhibitors (ADMET profile) Property Model Name Reference Minocycline CD38 inhibitor 78c Niraparib Unit Lipinski rule of 5 Molecular Weight ≤ 500 457.483 413.543 320.396 Numeric (log g/mol) LogP ≤ 5 0.03 4.0481 2.5914 Numeric (MLogP) Rotatable Bonds ≤ 10 3 7 3 Numeric (RB) Acceptors Hydrogen ≤ 10 9 7 4 Numeric (AH) Donors Hydrogen ≤ 5 5 1 2 Numeric (DH) Molar refractivity 40–130 119.14 118.4 97.96 Numeric (MR) TPSA < 140 164.63 93.62 72.94 Numeric (Å) Absorption Water solubility <−10 < poorly soluble <−6 < moderately soluble <−4 < soluble <−2 < very soluble < 0 0.90 0.643 0.701 0.897 Numeric (log Papp in 10 − 6 cm/s) Absorption Intestinal absorption (human) Low: 0–20% Medium: 20–70% High: 70–100% 39.368 95.326 94.432 Numeric (% Absorbed) Absorption Skin Permeability Likely skin permeable >-2.5 -2.741 -2.758 -2.97 Numeric (log Kp) Absorption P-glycoprotein substrate Yes Yes Yes Yes Categorical (Yes/No) Absorption P-glycoprotein I inhibitor No No Yes No Categorical (Yes/No) Absorption P-glycoprotein II inhibitor No No Yes Yes Categorical (Yes/No) Distribution VDss (human) Low 0.45 0.429 0.512 0.861 Numeric (log L/kg) Distribution Fraction unbound (human) - 0.483 0.165 0.164 Numeric (Fu) Distribution BBB permeability > 0.3 (readily cross BBB) -2 (penetrate CNS) <-3(cannot penetrate CNS) -3.613 -2.367 -2.126 Numeric (log PS) Metabolism CYP2D6 substrate No No No No Categorical (Yes/No) Metabolism CYP3A4 substrate No No Yes Yes Categorical (Yes/No) Metabolism CYP1A2 inhibitior No No Yes Yes Categorical (Yes/No) Metabolism CYP2C19 inhibitior No No Yes No Categorical (Yes/No) Metabolism CYP2C9 inhibitior No No Yes No Categorical (Yes/No) Metabolism CYP2D6 inhibitior No No No Yes Categorical (Yes/No) Metabolism CYP3A4 inhibitior No No Yes No Categorical (Yes/No) Excretion Total Clearance -0.002 0.263 0.569 0.868 Numeric (log ml/min/kg) Excretion Renal OCT2 substrate No No Yes No Categorical (Yes/No) Toxicity AMES toxicity No No No No Categorical (Yes/No) Toxicity Max. tolerated dose (human) Low ≤ 0.477 High > 0.477 0.127 -0.575 -0.138 Numeric (log mg/kg/day) Toxicity hERG I inhibitor No No No No Categorical (Yes/No) Toxicity hERG II inhibitor No No Yes Yes Categorical (Yes/No) Toxicity Oral Rat Acute Toxicity (LD50) - 2.025 2.397 2.449 Numeric (mol/kg) Toxicity Oral Rat Chronic Toxicity (LOAEL) - 3.309 0.693 1.453 Numeric (log mg/kg bw/day) Toxicity Hepatotoxicity No No Yes Yes Categorical (Yes/No) Toxicity Skin Sensitization No No No No Categorical (Yes/No) Toxicity T.Pyriformis toxicity Toxic: >-0.05 0.285 0.438 0.745 Numeric (log ug/L) Toxicity Minnow toxicity Toxic: >-0.3 4.829 1.354 1.892 Numeric (log mM) TPSA = Topological polar surface area, RB = Rotatable bond, AH = Acceptors Hydrogen, DH = Donor Hydrogen, and MR – Molar refractivity 3.2 Membrane Permeability Prediction Fig 2A illustrates the conformational dynamics of minocycline and the standard inhibitors during their translocation across the cell membrane. Each compound adapted its orientation in response to the membrane’s hydrophilic and hydrophobic regions. Niraparib demonstrated the lowest membrane penetration energy, indicating more favorable translocation, whereas minocycline exhibited the highest energy, suggesting less efficient membrane permeability. 3.3 Binding site prediction In this study, the binding pocket of 4CMH (CD38) had a surface area of 904.081 Å2 and a volume of 891.237 Å3 while that of 4L7N (PARP2) was 483.423 Å2 and 419.887 Å3 as predicted by the CASTP server. These pockets contained the following residues (Table 4 ), Table 4 Area and volume of binding pocket and residues within the pocket as predicted by CASTP server. PDB ID (Protein) Area (Å2) Volume (Å3) Residues 4CMH (CD38) 904.081 891.237 GLY 52, PRO 53, LEU 123, LEU 124, TRP 125, SER 126, ARG 127, LYS 129, LEU 145, GLU 146, ALA 154, ASP 155, ASP 156, LEU 157, THR 158, TRP 159, CYS 173, PRO 174, ASP 175, TRP 176, ARG 177, SER 181, ASN 182, ASN 183, PRO 184, VAL 185, SER 186, VAL 187, TRP 189, LYS 190, SER 193, PHE 196, ASP 217, ASP 219, SER 220, THR 221, PHE 222, GLU 226. 4L7N (PARP2) 483.423 419.887 LYS 223, ILE 226, PHE 230, GLN 280, ASP 284, LEU 287, VAL 288, ALA 290, ASP 291, GLU 293, LEU 294, HIS 384, GLY 385,THR 386, ASN 387, VAL 390, ILE 394, LEU 399, ARG 400, ILE 401, MET 402, PRO 403, HIS 404, SER 405, GLY 406, GLY 407, ARG 408, GLY 410, LYS 411, GLY 412, ILE 413, TYR 414, PHE 415, ALA 416, LYS 421, SER 422, TYR 425, GLU 514. 3.4 Molecular docking In the present study, we observed a slight increase in the binding affinity (lower binding energy (kcal/mol) of minocycline (-8.9 Kcal/mol) for CD38 in comparison with the binding affinity of the standard inhibitor CD38 inhibitor 78c (-8.4 Kcal/mol). Similarly, a slightly higher binding affinity was observed between minocycline (-10.2 Kcal/mol) and PARP2 in comparison with that of the standard inhibitor Niraparib (-10.1 Kcal/mol) (Fig. 3Ai and 3Aii). These values were derived from the best pose of the minocycline and the standard inhibitors within the binding pockets of CD38 and PARP2 (Fig. 3Bi and 3Bii) 3.5 Characterization of protein-ligand interaction Interaction mapping between target protein residues and the top-scoring ligands was performed to identify key intermolecular bonds involved in binding (Sivani et al., 2021 ). Minocycline formed hydrogen bond interaction at THR221, SER186, GLU146, LEU157, and TYR414 and hydrophobic interaction at VAL185 and TRP125 with CD38 while CD38 inhibitor 78c formed hydrogen bond interaction at ASP156, TRP176, LYS190, PHE222, TRP125 and GLU226 and hydrophobic interaction with TRP125, TRP176 and TRP189 with CD38 at respective bond lengths (Å) (Table 5 ). The result revealed no similarity in hydrogen bond interaction between minocycline and the standard inhibitor with CD38, however, both compounds had hydrophobic interaction with TRP125 of CD38. The interaction between minocycline and PARP2 was constituted of hydrogen bond at THR386, ASN387, TYR425 and TYR414 and hydrophobic interaction at TYR414 and TYR425. In addition, Niraparib formed hydrogen bond with PARP2 at ASP291 and PHE415 and hydrophobic bond at HIS384, TYR414, TYR425, LEU287, VAL288 and VAL390 at respective bond lengths (Å) as presented in (Table 5 ). No similarity in hydrogen bond interaction between minocycline and the standard inhibitor with CD38 was seen, however, both compounds had hydrophobic interaction with PARP2 at TYR414 and TYR425. Figures 4 A–D and 5 A–D present the 2D and 3D interaction profiles between minocycline, the standard inhibitors, and the amino acid residues of CD38 and PARP2 for better interpretation. 3.6 Prediction of Potential Bioactivity Originally classified as an antibiotic, minocycline also exhibits various biological activities beyond its antimicrobial properties. The results confirmed that most medium to high probability scores (Pa between 0.3 and 0.66) correlated with mechanisms underlying minocycline's antibiotic effects. Notably, minocycline was also predicted to influence NAD + levels and modulate the activity of CD38 and PARPs by inhibiting enzymes such as NAD + -dinitrogen-reductase ADP-D-ribosyltransferase, NAD(P) + -arginine ADP-ribosyltransferase, glutamate dehydrogenase, glutamate-5-semialdehyde dehydrogenase, protein tyrosine phosphatase, and cytokine release. However, these predictions indicated a weaker activity profile (Pa Pi values). Similarly, Niraparib, aside from its role in inhibiting PARPs, showed potential for inhibiting NAD + -dinitrogen-reductase ADP-D-ribosyltransferase (Pa = 0.26), glutamate-5-semialdehyde dehydrogenase (Pa = 0.57), and protein tyrosine 2C phosphatase (Pa = 0.07). In contrast to minocycline, CD38 inhibitor 78c appears to regulate NAD + levels by inhibiting coactivator-associated arginine methyltransferase 1 (Pa = 0.142) and cyclin-dependent kinase (Pa = 0.098) (Table 6 ). Table 6 Predicted biological activity of minocycline and standard inhibitors of CD38 and PARPs Compound Activity Pa Pi Minocycline NAD+-dinitrogen-reductase ADP-D-ribosyltransferase inhibitor NAD(P)+-arginine ADP-ribosyltransferase inhibitor Glutamate dehydrogenase inhibitor Glutamate-5-semialdehyde dehydrogenase inhibitor Protein-tyrosine phosphatase inhibitor Cytokine release inhibitor 0.1930.219 0.169 0.294 0.171 0.097 0.029 0.192 0.026 0.176 0.033 0.051 CD38 inhibitor 78c Coactivator-associated arginine methyltransferase 1 inhibitor Cyclin-dependent kinase 6 inhibitor 0.1420.098 0.023 0.059 Niraparib NAD+-dinitrogen-reductase ADP-D-ribosyltransferase inhibitor Glutamate-5-semialdehyde dehydrogenase inhibitor Protein-tyrosine phosphatase 2C inhibitor 0.263 0.571 0.065 0.027 0.046 0.042 3.7 Metabolic pathway analysis From the Kegg database, CD38 is involved in nicotinate and nicotinamide metabolism, with matching proteins including SIRT4, SIRT1, NAMPT, NUDT12, NNT, BST1, NMNAT2, NMRK1, NMNAT1, NADK2, SIRT3, NAPRT, ENPP3, and NNMT. CD38 may modulate NAD + levels influencing various metabolic pathways, associated with the same set of proteins. Additionally, CD38 is expressed on hematopoietic cells impacting their differentiation and activation, with matching proteins including CD4, CD38, CD34, and CD19. It also indirectly affects riboflavin metabolism through the regulation of NAD + and related proteins such as ENPP3 and ENPP1. By maintaining NAD + homeostasis, CD38 influences pantothenate and CoA biosynthesis, also associated with ENPP3 and ENPP1. Furthermore, CD38 may contribute to cell adhesion processes via immune signaling modulation, again linked to proteins CD4, CD34, and PECAM1. Lastly, dysregulation of CD38 is associated with impaired immune responses contributing to primary immunodeficiency, with relevant proteins including CD4 and CD19. The result also revealed that PARP2 is involved in base excision repair, with matching proteins including PARP2, XRCC1, POLB, PARP1, and LIG3. PARP2 is also linked to apoptosis, associated with proteins PARP2, CASP3, and PARP1. Additionally, PARP2 plays a role in viral carcinogenesis, with relevant proteins POLB, CASP3, and H2BC11, indicating its potential involvement in the cellular response to viral infections and their ability to induce cancer (Table 7 ). 3.8 Analysis of Protein-protein interaction (PPI) Network Protein-protein interaction (PPI) network analysis conducted via the STRING database revealed significant functional associations involving CD38 and several key proteins, including SIRT1, SIRT3, NAMPT, ENPP1, NMNAT1, NMNAT2, CD19, CD3, CD4, and PECAM1. Notably, CD38 exhibited strong interaction with NAMPT, an enzyme critical for the conversion of nicotinamide to NMN, a precursor in the biosynthesis of NAD + . Furthermore, it showed interactions with SIRT1 and SIRT3, both of which are NAD + -dependent deacetylases (Fig. 6 A). For PARPs, significant protein-protein interactions involving PARP2 and several critical proteins: H2AC6, HPF1, H2BC11, PARG, PARP1, POLB, LIG3, XRCC1, XRCC6, and CASP3 was observed. Notably, PARP2 demonstrated a strong interaction with PARP1 (Fig. 6 B). 3.9 Molecular Dynamics Simulation All protein-ligand systems achieved structural stability, with protein backbone RMSD values falling within ranges typical of equilibrated globular proteins. For CD38, the average protein RMSD for the minocycline complex was lower with smaller fluctuations in comparison to the CD38 inhibitor 78C complex (Fig. 7 – 8 A and B). Similarly, for PARP2, the minocycline complex exhibited a lower average protein RMSD compared to the niraparib complex, with fluctuations within the same range in both systems (Fig. 7 – 8 C and D). Ligand RMSD and RMSF analyses consistently revealed that minocycline maintained more stable and rigid binding than either CD38 inhibitor 78C or niraparib. In the CD38 system, minocycline showed lesser ligand RMSD values and RMSF values in comparison to the CD38 inhibitor 78C which showed more variability in ligand RMSD and RMSF (Figs. 7 & 9 A and B). Similarly, in the PARP2 system, minocycline exhibited lower RMSD and RMSF values in comparison to niraparib (Figs. 7 & 9 C and D). For the protein-ligand interaction minocycline consistently formed more hydrogen bonds across both systems. Specifically, minocycline showed sustained interaction for over 70% of the simulation time with LYS 190. In contrast, CD38 inhibitor 78C and niraparib formed fewer hydrogen bonds, with more transient contacts spread across multiple residues. Although niraparib showed reduced number of hydrogen bonds, it revealed sustained interaction for over 70% of the simulation time with ARG 400 and GLU 514. Hydrophobic interactions were more pronounced in the standard inhibitors. Water bridges were observed in all systems but occurred more frequently in the minocycline complexes, enhancing their polar stabilization (Fig. 10 A-D). Torsional analyses showed that minocycline adopted more constrained bound conformations. Across its six rotatable bonds, minocycline's dihedral angles were narrowly distributed, while CD38 inhibitor 78C and niraparib, with seven and four rotatable bonds respectively, demonstrated broader torsional flexibility, reflecting greater conformational entropy (Fig. 11 ). The radius of gyration (rGyr) remained stable across all ligands. Solvent exposure analysis showed higher SASA across both proteins (Fig. 12 ). Discussion Chronic activation of CD38 and PARPs, particularly with advancing age, exacerbates NAD⁺ decline, impairing cellular activity and accelerating ageing-related pathologies. Thus, identifying compounds capable of modulating both targets could mitigate the ageing process through preservation of NAD + levels (Camacho-Pereira et al., 2016 ; Covarrubias et al., 2021 ). An ideal oral drug should be absorbed, distributed, metabolized without losing its activity, excreted and without toxicity (Stielow et al., 2023 ). The pharmacokinetic and pharmacodynamic profiling of minocycline and the standard inhibitors (CD38 inhibitor 78c and Niraparib), revealed that they all demonstrated high drug-likeness potential, meeting RoF. However, minocycline was the only compound that exceeded the total polar surface area (TPSA) threshold (> 140), which can impact cell membrane permeability, potentially limiting its absorption (Matsson & Kihlberg, 2017 ). Minocycline and the standard inhibitors displayed good to very good water solubility, with minocycline demonstrating lower absorption levels compared to standard inhibitors based on Caco-2 permeability and intestinal absorption predictions. In terms of skin permeability, minocycline and the standard inhibitors exhibited a consistent log Kp >-2.5, indicating limited skin permeability. This property may impact potential transdermal applications but is unlikely to affect the drug’s activity in oral administration. Distribution parameters highlighted significant variability among minocycline and the standard inhibitors. The distribution volume (VDss) for minocycline was moderate, whereas the standard inhibitors displayed very high distribution volumes, suggesting that the standard inhibitors may have broader tissue distribution. Blood-brain barrier permeability (logBB) was below 0.3 for minocycline and the standard inhibitors, indicating poor ability to cross the blood-brain barrier (Fong, 2015 ), which could limit central nervous system (CNS) side effects. CNS permeability, as indicated by logPS values < -2, suggested that minocycline and the standard inhibitors were poorly CNS-penetrant, a property that could be advantageous in reducing off-target CNS effects. Minocycline, and the standard inhibitors, were identified as substrate of P-glycoprotein, a key transporter involved in cellular drug efflux (Sharom, 2011 ). CD38 inhibitor 78c inhibits P-glycoprotein I, whereas Niraparib was found to inhibit both P-glycoprotein I and II. These findings suggest that the inhibitors may differ in how they interact with drug transport pathways, potentially influencing their bioavailability and distribution within cells (Zhao et al., 2021 ). Minocycline showed no inhibitory effects on CYP enzymes, suggesting a potentially lower risk of metabolic interactions, whereas CD38 inhibitor 78c and Niraparib were substrates and inhibitors of several CYP enzymes, including CYP1A2, CYP2C19, CYP2C9, and CYP3A4. These findings suggest a significant risk of drug-drug interactions, particularly in patients taking other medications metabolized by cytochrome P450 (CYP) enzymes. Minocycline and the standard inhibitors showed high clearance rates, which, together with their hydrophilic nature and molecular size, may support their efficient elimination from the body. According to AMES toxicity predictions, all compounds were classified as non-mutagenic. However, the standard inhibitors—CD38 inhibitor 78c and Niraparib—were associated with greater safety concerns, showing potential hepatotoxicity and neurotoxicity. Additionally, Niraparib presented a moderate risk for carcinogenicity. Despite these in silico findings, further in vivo research is essential to determine the dosage thresholds at which these compounds exert therapeutic benefits versus harmful effects. Minocycline demonstrated a marginally higher binding affinity for both CD38 and PARP2 when compared to the standard inhibitors, suggesting its potential as a modulator of these NAD⁺-consuming enzymes. The increase in the binding affinity implies that minocycline may form stable interactions with the active sites of these proteins, potentially influencing their enzymatic activity. The possible inhibitory effect of minocycline on both CD38 and PARP2, two enzymes with central role in age-related NAD⁺ depletion, may have therapeutic relevance, particularly in ageing populations (Covarrubias et al., 2021 ). Decline of intracellular NAD⁺ levels during ageing, have been associated with disruption in mitochondrial function, energy metabolism, and cellular repair mechanisms. By effectively interacting with these enzymes, minocycline may help preserve NAD⁺ availability, thereby supporting metabolic health and neuroprotection (Amjad et al., 2021 ). These observations are in line with prior studies, where pharmacological inhibition of CD38 using the CD38 inhibitor 78c led to improved metabolic outcomes and restored tissue NAD⁺ levels in aged mice (Tarragó et al., 2018 ). Similarly, inhibition of PARP enzymes has been shown to confer neuroprotective benefits. Olaparib, a PARP inhibitor, reduced brain damage in a mouse model of transient cerebral ischemia (Teng et al., 2016 ), while INO1001 mitigated neuronal degeneration in models of spinal cord injury and Huntington’s disease (Cardinale et al., 2015 ). Minocycline formed hydrogen bonds at specific residues with CD38 (THR221, SER186, GLU146, LEU157, and TYR414) and exhibited hydrophobic interactions at VAL185 and TRP125, whereas the CD38 inhibitor 78c displayed hydrogen bonding at different residues and shared only the hydrophobic interaction at TRP125 with minocycline. A similar pattern was observed with PARP2, where minocycline and Niraparib shared hydrophobic interactions at TYR414 and TYR425 but exhibited different hydrogen bond interactions. These shared hydrophobic sites suggest that minocycline may mimic aspects of the binding behaviour of the standard inhibitors. Overall, this study suggests that minocycline could serve as a potential therapeutic strategy for counteracting NAD + depletion in ageing, though experimental validation is necessary to confirm these in silico findings as well as assess the physiological relevance. Niraparib, showed the lowest transfer energy, suggesting greater permeability across the lipid bilayer in comparison to minocycline and CD38 inhibitor 78c. This increased permeability provides Niraparib with access to the nuclear compartments where PARPs are located, thus, facilitating repair of the DNA (Vasil’eva et al., 2021 ). Conversely, minocycline had the greatest transfer energy through the lipid bilayer, suggesting decreased permeabilities across membranes. The decrease in permeation of minocycline through the cell membrane implies that it may have appropriate inhibitory effect on the cell surface, where CD38 is mainly found (Shrimp et al., 2014 ). This makes minocycline a fine candidate for specific targeting of CD38. However, to target PARP2 within the nucleus, minocycline may require being in complex with transport proteins to ease cell entry (Vasil’eva et al., 2021 ). Predicting the biological activity of minocycline and the standard inhibitors is essential in identifying their role in the regulation of the pathways associated with NAD + . Minocycline had a broad range of possible activities in comparison to the standard inhibitors. It is capable of binding to NAD + -dinitrogen-reductase ADP-D-ribosyltransferase and NAD(P) + -arginine ADP-ribosyltransferase, although, with less probabilities scores (Pa < 0.3) indicating that it might influence levels of NAD + indirectly. This is consistent with the corresponding binding affinities against PARPs and CD38, and further contributes to the possibility of repurposing it in NAD + -linked drug treatment. Niraparib and CD38 inhibitor 78c, however, had more specific profile similar to their respective known drug targets. Niraparib, exhibited moderate ability to inhibit glutamate-5-semialdehyde dehydrogenase (Pa = 0.57), which could suggest additional metabolic regulatory effect. In contrast, CD38 inhibitor 78c showed expected activity on enzymes coactivator-associated arginine methyltransferase 1, confirming its specificity for the modulation of CD38-involving NAD + pathways. The wider range of activity profile of minocycline may suggest that it has the potential to target many pathways of NAD + metabolism and as such can yield therapeutic benefits, particularly in overcoming the multifaceted age-related decrease in NAD + levels. Using the KEGG database valuable insights into the biological roles of the target proteins CD38 and PARP2 were further elucidated. CD38 was revealed to be involved in nicotinate and nicotinamide metabolism. It was also shown to interact with SIRT1, SIRT3, and NMNAT1, underscoring its central role in maintaining cellular levels of NAD + . PARP2 which is predominantly found in the nucleus, where it plays a pivotal role in base excision repair (Vasil’eva et al., 2021 ) was revealed to play a role in recruiting proteins like XRCC1 and POLB to sites of DNA damage using NAD + -dependent poly(ADP-ribosyl)ation. CD38’s was also shown to influence metabolic pathways with proteins such as ENPP1 and ENPP3, linking NAD + metabolism to riboflavin and pantothenate biosynthesis, suggesting that CD38 could have broad systemic impact. Similarly, PARP2 was associated with apoptosis and viral carcinogenesis, through CASP3 and H2BC11, underscoring its importance in maintaining genomic stability and cellular response to stress. PARP2 also interacted with XRCC1 and LIG3 further supporting its role in the base excision repair pathway (Lee & Lee, 2025 ). Additionally, its interaction with HPF1 a protein essential for enhancing the specificity of ADP-ribosylation by PARPs, further influences NAD + utilization. The interaction of PARP2 with histones (H2AC6 and H2BC11) suggests its role in changing chromatin structure, a fundamental component of DNA repair and transcriptional regulation. The PPI network analysis further buttresses report from the KEGG database. CD38 interacted with NAMPT, SIRT1, and SIRT3, further supporting its pivotal role in regulating NAD + levels and linking metabolism to immune signaling pathways (Yang et al., 2022 ). This suggests that in ageing and age-related diseases where CD38 is upregulated and NAD + levels are compromised, targeting CD38 could influence both metabolic homeostasis and immune cell function. PARP2 also interacted with PARP1, XRCC1, and LIG3 emphasizing its critical role in the DNA damage response and base excision repair which consume NAD + . The analysis of protein-ligand interactions revealed that minocycline had lower RMSD and RMSF values, suggestive of a more stable complex with both CD38 and PARP2. This suggest that minocycline may offer more sustained inhibition (Ogunyemi et al., 2025 ) of NAD + -consuming enzymes, and may have significant implications for the treatment of age-related diseases associated with NAD + decline (Covarrubias et al., 2021 ). Minocycline formed more hydrogen bonds and water bridges which are crucial for stabilizing the protein-ligand complex and ensuring effective target interaction (Chen et al., 2023 ) in comparison to CD38 inhibitor 78C and niraparib, with more lesser interactions. Increased stability of minocycline in this study in comparison to the standard inhibitors suggests that minocycline could provide more consistent and durable inhibition of CD38 and PARP2, thereby potentially preserving cellular level of NAD + . Previous studies have associated the higher stability and polarity of minocycline to its significant ability to cross the blood-brain barrier, (Yun et al., 2017 ; Asadi et al., 2020 ), although contrasting with observations in this study, where reduced permeation through the blood brain barrier was seen. The torsional analysis indicated that minocycline had a more constrained conformation compared to the standard inhibitors, with greater flexibility in their binding modes. This reduced conformational change suggests that minocycline may exert more stable and predictable effects, improving the feasibility of its use for long-term. The solvent-accessible surface area (SASA) defined by the van der Waals contact surface of the protein and the center of the hypothetical solvent sphere provides insight into how exposed a ligand is to the surrounding solvent while bound to its target (Ogunyemi et al., 2025 ). Higher SASA values typically suggest that more of the ligand’s surface is in contact with the aqueous environment. In contrast, lower SASA values indicate that a greater portion of the ligand is buried within the protein’s binding pocket, which often correlates with stronger hydrophobic interactions (Marsh & Teichmann, 2011 ; Metin & Kawano, 2025 ). The increased SASA observed in the minocycline-CD38 and minocycline-PARP2 complexes suggests that minocycline had both binding pockets exposed to solvent. In developing anti-aging drugs, where modulation rather than full inhibition of enzymes like CD38 and PARP2 might be preferable, minocycline’s partially solvent-exposed conformation may create an equilibrium between efficacy and safety. Hence, its desirability for long-term interventions. The radius of gyration evaluates the structural compactness of protein–ligand complexes throughout the simulation (Ogunyemi et al., 2025 ). The radius of gyration remained stable for minocycline and the standard inhibitors demonstrating their stability and compactness. Conclusion In conclusion, the findings from this study suggest that minocycline may possess therapeutic effects in the regulation of NAD + metabolism. Its stable binding to NAD + -consuming enzymes (CD38 and PARP2), suggest that it may preserve NAD + levels which decline with age, hence, could slow down ageing and the onset of age-related diseases. Further in vivo studies, are required to validate these findings and to evaluate the long-term impact of minocycline on NAD⁺ homeostasis and the ageing process. If validated, minocycline may emerge as a versatile therapeutic candidate, targeting critical ageing pathways and potentially enhancing healthspan while mitigating age-associated deterioration. Declarations Acknowledgements Not Applicable. Ethics approval and consent to participate Not applicable. Funding The research was partly funded by the Institution Based Research grant by Tetfund (REF: TETF/DR&D/UNI/ZARIA/IBR/2020/VOL.1/53) Data Availability All datasets analyzed during this study are included within the manuscript. Competing Interests The authors declare no conflicts of interest related to the research, authorship, or publication of this article. Authors’ Contributions Oluwasegun Davis Olatomide (ODO), Sunday Abraham Musa (SAM), and Amos Olalekan Abolaji (AOA) were responsible for conceptualization and design of the study. ODO, Zainab Mahmood Bauchi (ZMB), Sohnap James Sambo (SJS), Abel Nosereme Agbon (ANA), wrote and edited the manuscript. ODO and Akinyemi Ademola Omoniyi (AAO) performed the data curation and analysis. SAM and AOA reviewed and edited the final version of the manuscript. All authors read and approved the final manuscript References Alfarado, D., Shiyan, S., & Ferlinahayati, F. 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Rapamycin Modulates Tissue Aging and Lifespan Independently of the Gut Microbiota in Drosophila. Scientific Reports, 9 (1), 7824. doi:10.1038/s41598-019-44106-5 Schrödinger, L. (2021). Schrödinger Release 2022-3: Ligprep. Schrödinger, LLC: New York, NY, USA . Sharom, F. J. (2011). The P-Glycoprotein Multidrug Transporter. Essays in biochemistry, 50 , 161-178. Shrimp, J. H., Hu, J., Dong, M., Wang, B. S., MacDonald, R., Jiang, H., Hao, Q., Yen, A., & Lin, H. (2014). Revealing Cd38 Cellular Localization Using a Cell Permeable, Mechanism-Based Fluorescent Small-Molecule Probe. Journal of the American Chemical Society, 136 (15), 5656-5663. Sivani, B. M., Venkatesh, P., Murthy, T. K., & Kumar, S. B. (2021). In Silico Screening of Antiviral Compounds from Moringa Oleifera for Inhibition of Sars-Cov-2 Main Protease. Current Research in Green and Sustainable Chemistry, 4 , 100202. Stielow, M., Witczynska, A., Kubryn, N., Fijalkowski, L., Nowaczyk, J., & Nowaczyk, A. (2023). 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Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep, 6 , 26933. doi:10.1038/srep26933 Vasil’eva, I., Moor, N., Anarbaev, R., Kutuzov, M., & Lavrik, O. (2021). Functional Roles of Parp2 in Assembling Protein–Protein Complexes Involved in Base Excision DNA Repair. International Journal of Molecular Sciences, 22 (9), 4679. Wahono, C. S., Syaban, M. F. R., Pratama, M. Z., Rahman, P. A., & Erwan, N. E. (2024). Exploring the Potential of Phytoconstituents from Phaseolus Vulgaris L against Cxc Motif Chemokine Receptor 4 (Cxcr4): A Bioinformatic and Molecular Dynamic Simulations Approach. Egyptian Journal of Medical Human Genetics, 25 (1), 52. Waters, K. L., & Spratt, D. E. (2024). New Discoveries on Protein Recruitment and Regulation During the Early Stages of the DNA Damage Response Pathways. International Journal of Molecular Sciences, 25 (3), 1676. Yang, Q., Luo, L., Sun, T., Yang, L., Cheng, L.-F., Wang, Y., Liu, Q.-Q., Liu, A., Liu, H.-Y., & Zhao, M.-G. (2020). Chronic Minocycline Treatment Exerts Antidepressant Effect, Inhibits Neuroinflammation, and Modulates Gut Microbiota in Mice. Psychopharmacology, 237 , 3201-3213. Yang, Y., Liu, Y., Wang, Y., Chao, Y., Zhang, J., Jia, Y., Tie, J., & Hu, D. (2022). Regulation of Sirt1 and Its Roles in Inflammation. Frontiers in immunology, 13 , 831168. Yoshino, J., Baur, J. A., & Imai, S.-i. (2018). Nad+ Intermediates: The Biology and Therapeutic Potential of Nmn and Nr. Cell Metab, 27 (3), 513-528. Yousefzadeh, M., Henpita, C., Vyas, R., Soto-Palma, C., Robbins, P., & Niedernhofer, L. (2021). DNA Damage—How and Why We Age? elife, 10 , e62852. Yun, H. M., Noh, S., & Hyun, S. (2017). Minocycline Treatment Suppresses Juvenile Development and Growth by Attenuating Insulin/Tor Signaling in Drosophila Animal Model. Scientific reports, 7 (1), 44724. Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D'Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., Schoonjans, K., Menzies, K. J., & Auwerx, J. (2016). Nad? Repletion Improves Mitochondrial and Stem Cell Function and Enhances Life Span in Mice. Science, 352 (6292), 1436-1443. doi:10.1126/science.aaf2693 Zhao, M., Ma, J., Li, M., Zhang, Y., Jiang, B., Zhao, X., Huai, C., Shen, L., Zhang, N., & He, L. (2021). Cytochrome P450 Enzymes and Drug Metabolism in Humans. International Journal of Molecular Sciences, 22 (23), 12808. Zhou, S., Li, D., Quan, C., Yu, Z., Feng, Y., Wang, S., Li, Y., Qi, T., & Chen, J. (2025). Pan-Cancer Profiling of Fzd2 as a Prognostic Biomarker: Integrative Multi-Omics Analysis with Experimental Validation and Functional Characterization in Gastric Cancer. Frontiers in Pharmacology, 16 , 1534974. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7474241","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":506583882,"identity":"4cc1b560-22c0-4738-ae59-f199cadca451","order_by":0,"name":"Oluwasegun Davis Olatomide","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYDACdjApwdjAwHwAInKAkBZmBqBqsBa2BJK0gAgeA+K08DMzP3/wMcdCtp+959tn3h0Mcnw3EtgefsGjRbKZzbBx5jYJ45k9ZzfP5j3DYCx5I4HdWAaPFoPDDIbNvNskEjfcyN3MzNvGAGQksElL4NXC/hGsZf+NnMcgLfVEaOGB2iKRwwzSkmAA1CL5Aa9feApngvwy48wxY8a5bRKGM888bJPGo4OBn719w4eP2+pk+9ubHzO8bbOR5zuefEzyBz49aADkCcYGZh4StEAAIym2jIJRMApGwbAHAFWPS1iNljR/AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4596-3348","institution":"Redeemer’s University, Ede","correspondingAuthor":true,"prefix":"","firstName":"Oluwasegun","middleName":"Davis","lastName":"Olatomide","suffix":""},{"id":506583971,"identity":"98b5d9c9-1f9d-4d86-a77a-b49d468b8af0","order_by":1,"name":"Sunday Abraham Musa","email":"","orcid":"https://orcid.org/0000-0003-3097-9355","institution":"Ahmadu Bello University, Zaria","correspondingAuthor":false,"prefix":"","firstName":"Sunday","middleName":"Abraham","lastName":"Musa","suffix":""},{"id":506584030,"identity":"da54adb4-7c4e-4a9b-9049-2ecce2c0369c","order_by":2,"name":"Zainab Mahmood Bauchi","email":"","orcid":"https://orcid.org/0000-0002-1109-4378","institution":"Abubakar Tafawa Balewa University","correspondingAuthor":false,"prefix":"","firstName":"Zainab","middleName":"Mahmood","lastName":"Bauchi","suffix":""},{"id":506584031,"identity":"e30049d0-ff08-4ba2-8e41-5a07919f6b4c","order_by":3,"name":"Sohnap James Sambo","email":"","orcid":"https://orcid.org/0000-0002-2530-8322","institution":"Ahmadu Bello University, Zaria","correspondingAuthor":false,"prefix":"","firstName":"Sohnap","middleName":"James","lastName":"Sambo","suffix":""},{"id":506584044,"identity":"2a23ea4e-a8fe-4a45-80b3-624bb0ce345c","order_by":4,"name":"Abel Nosereme Agbon","email":"","orcid":"https://orcid.org/0000-0003-1390-8133","institution":"Ahmadu Bello University, Zaria","correspondingAuthor":false,"prefix":"","firstName":"Abel","middleName":"Nosereme","lastName":"Agbon","suffix":""},{"id":506585706,"identity":"8075c79b-e7c4-4543-a0fb-bd61d01911af","order_by":5,"name":"Akinyemi Ademola Omoniyi","email":"","orcid":"https://orcid.org/0000-0002-3436-7340","institution":"Ahmadu Bello University, Zaria","correspondingAuthor":false,"prefix":"","firstName":"Akinyemi","middleName":"Ademola","lastName":"Omoniyi","suffix":""},{"id":506585707,"identity":"e88620db-9ec9-49de-bace-f7fec34323d9","order_by":6,"name":"Amos Olalekan Abolaji","email":"","orcid":"https://orcid.org/0000-0002-4203-452X","institution":"University of Ibadan","correspondingAuthor":false,"prefix":"","firstName":"Amos","middleName":"Olalekan","lastName":"Abolaji","suffix":""}],"badges":[],"createdAt":"2025-08-27 18:56:21","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7474241/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7474241/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90145732,"identity":"3a9a3351-8c77-454b-bfca-9e2138177906","added_by":"auto","created_at":"2025-08-29 05:38:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23988,"visible":true,"origin":"","legend":"\u003cp\u003eA) Lipinski Rule of 5 represented by yellow and purple code indicating fulfilled or not fulfilled respectively B) Toxicity analysis evaluated mutagenicity, carcinogenicity, cytotoxicity, and organ-specific toxicities including nephrotoxicity, neurotoxicity, cardiotoxicity, and respiratory toxicity parameters. Each parameter was classified using a risk scale: 0 for no risk (green), 0.5 for moderate risk (black), and 1 for high risk (red).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/bf92828482d63ce9d3e282fe.png"},{"id":90146830,"identity":"2efc8120-6ef1-4e82-817f-2ab1018734de","added_by":"auto","created_at":"2025-08-29 05:54:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":90615,"visible":true,"origin":"","legend":"\u003cp\u003eA and B) Permeability analysis revealed the translocation energy of each compound across the lipid bilayer membrane\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/2990682b87a6fff11d7ea957.png"},{"id":90145728,"identity":"8cab7f64-7f94-4894-ae76-f2fc2615258e","added_by":"auto","created_at":"2025-08-29 05:38:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":194011,"visible":true,"origin":"","legend":"\u003cp\u003eA. Docking score (Binding affinity (Kcal/mol)) from docking of i) minocycline and CD38 inhibitor 78c against CD38 ii) minocycline and Niraparib against PARP2. B. 3D representation of i) minocycline (yellow) and CD38 inhibitor 78c in CD38 binding pocket ii) minocycline and Niraparib in PARP2 binding pocket.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/e226f60e2d18f462f34c885c.png"},{"id":90147009,"identity":"096b7b6d-6436-48b9-b636-15292988939e","added_by":"auto","created_at":"2025-08-29 06:02:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":194307,"visible":true,"origin":"","legend":"\u003cp\u003eBinding pocket and ligand interactions are shown in panels A and C, depicting the 3D structures of minocycline (yellow) and CD38 inhibitor 78c (red) bound to CD38, along with hydrophobicity surface mapping. The protein pocket region is slightly to very bluish which indicates hydrophilicity. Both ligands bind to the same pocket of the protein. Panels B and D display the 2D interaction diagrams of minocycline and CD38 inhibitor 78c with CD38, highlighting the key interacting residues.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/b416ae91f389452f8315ba09.png"},{"id":90145729,"identity":"2b30c438-3f52-4ff9-bd7a-7f5fb12b6119","added_by":"auto","created_at":"2025-08-29 05:38:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":200500,"visible":true,"origin":"","legend":"\u003cp\u003eBinding pocket and ligand interactions are shown in panels A and C, illustrating the 3D structures of minocycline (yellow) and niraparib (green) bound to PARP2, along with hydrophobicity surface mapping. The binding pocket displays a mix of brownish and bluish regions, indicating areas of hydrophobicity—more prominently in panel C. Both ligands occupy the same binding site within the protein. Panels B and D present the 2D interaction diagrams of minocycline and CD38 inhibitor 78c with CD38, highlighting key interacting residues.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/aa8651e98c7789d4f8213858.png"},{"id":90146282,"identity":"b38fb123-f4b9-447f-9052-d961aa7b95c6","added_by":"auto","created_at":"2025-08-29 05:46:04","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":174307,"visible":true,"origin":"","legend":"\u003cp\u003eThe PPI networks of (A) CD38 and (B) PARP2 demonstrate their roles in distinct regulatory processes and disease pathways. Interactions are visualized with green lines for gene neighborhoods, red for gene fusions, blue for gene co-occurrence, cyan for protein homology, and black for co-expression.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/93a1994921ccb898e7f67e23.png"},{"id":90146280,"identity":"7eab63f1-7894-4c5d-a9a0-06773410ec26","added_by":"auto","created_at":"2025-08-29 05:46:03","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":201801,"visible":true,"origin":"","legend":"\u003cp\u003eProtein–ligand root mean square deviation (RMSD) for a 100-nanosecond simulation using Desmond: (A) Minocycline-CD38 complex (B) CD38 inhibitor 78c-CD38 complex, (C) Minocycline-PARP2 complex (D) Niraparib-PARP2 complex.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/12b854a0a19067b3f58a4c42.png"},{"id":90145733,"identity":"f66d3174-8918-4f64-bee5-3d6230efcfec","added_by":"auto","created_at":"2025-08-29 05:38:03","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":124184,"visible":true,"origin":"","legend":"\u003cp\u003eProtein root mean square fluctuation (RMSF) for a 100-nanosecond simulation using Desmond: (A) Minocycline-CD38 complex (B) CD38 inhibitor 78c-CD38 complex, (C) Minocycline-PARP2 complex (D) Niraparib-PARP2 complex.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/9c95d9acef65fb8ee5b67d67.png"},{"id":90145739,"identity":"2fc88033-14a0-4340-a81d-a3e8a82f7a18","added_by":"auto","created_at":"2025-08-29 05:38:03","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":86848,"visible":true,"origin":"","legend":"\u003cp\u003eLigand root mean square fluctuation (RMSF) for a 100-nanosecond simulation using Desmond: (A) Minocycline-CD38 complex (B) CD38 inhibitor 78c-CD38 complex, (C) Minocycline-PARP2 complex (D) Niraparib-PARP2 complex.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/e0fdd8549ef1db1eb9887c56.png"},{"id":90145747,"identity":"7023ece1-1636-4d11-b1b4-37c5535f2701","added_by":"auto","created_at":"2025-08-29 05:38:04","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":100732,"visible":true,"origin":"","legend":"\u003cp\u003eHistogram depicting the frequency of protein–ligand contacts throughout the simulation trajectory: (A) Minocycline–CD38 complex, (B) CD38 inhibitor 78c–CD38 complex, (C) Minocycline–PARP2 complex, and (D) Niraparib–PARP2 complex\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/70f0461ef193622690dadbe0.png"},{"id":90145738,"identity":"9f902f1f-2d53-4756-8c54-02a7c7e6d20a","added_by":"auto","created_at":"2025-08-29 05:38:03","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":117314,"visible":true,"origin":"","legend":"\u003cp\u003eRadial and bar plots illustrating the changes in conformation of each rotatable bond (RB) in the ligands during the simulation: (A) Minocycline–CD38 complex, (B) CD38 inhibitor 78c–CD38 complex, (C) Minocycline–PARP2 complex, and (D) Niraparib–PARP2 complex.\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/e9407c1136a5aeb1baf2171e.png"},{"id":90146298,"identity":"a433d443-5914-4b90-b1a2-e50b922e1a16","added_by":"auto","created_at":"2025-08-29 05:46:04","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":200316,"visible":true,"origin":"","legend":"\u003cp\u003ePlots of Solvent Accessible Surface Area (SASA) and Radius of Gyration (Rg) over the simulation period for the protein–ligand complexes: (A) Minocycline–CD38, (B) CD38 inhibitor 78c–CD38, (C) Minocycline–PARP2, and (D) Niraparib–PARP2.\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/1fb3eefe336da563a6c9c116.png"},{"id":90147486,"identity":"f1a806b5-7cbd-4f9c-be83-aca1ad51eed0","added_by":"auto","created_at":"2025-08-29 06:10:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3151223,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/bca8673a-fdf5-4b05-be62-49a6f72d237f.pdf"},{"id":90146275,"identity":"bd8a8ba5-9e6b-4893-b34c-ef51e02a01d8","added_by":"auto","created_at":"2025-08-29 05:46:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":191538,"visible":true,"origin":"","legend":"","description":"","filename":"Table1and2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7474241/v1/4767483ff7dead4acd577480.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eTargeting Age-Associated NAD⁺ Decline: \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ein silico \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eEvaluation of Minocycline as an Inhibitor of CD38 and PARP2\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1.0 Introduction","content":"\u003cp\u003eDNA damage and genomic instability have been considered as major driving forces of rapid ageing (McKinnon, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). It is estimated that above 10,000 DNA lesions accumulate in each cell daily (Milano et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Accumulation of these lesions are caused by consistent exposure to endogenous agents, \u0026ldquo;including reactive nitrogen species (RNS), reactive oxygen species (ROS)\u0026rdquo;, and environmental sources, like carcinogens, radiation and chemical mutagens (Fakouri et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Carusillo \u0026amp; Mussolino, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHence, to maintain the normal function of the cell, repair in nucleotide, bases, single strand break and double strand breaks occur in cell (Chatterjee \u0026amp; Walker, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Polyzos et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Decline in the ability of the cell to repair DNA lesions occur as we age leading to its accumulation and blockage of DNA replication forks thus inhibiting cell cycle progression in proliferating cells (Yousefzadeh et al., \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Herr et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Just like the repair proteins, recruitment proteins are also important in response to DNA damage (Waters \u0026amp; Spratt, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). When DNA damage occurs, it activates poly(ADP-ribose) polymerases (PARPs), which utilize NAD⁺ to add ADP-ribose chains to DNA and nearby proteins. This modification acts as an early signal to attract and assemble DNA repair proteins at the site of damage (Bai, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Braidy et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Demarest et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAs organisms age, impairments in DNA repair mechanisms allow damage to accumulate, resulting in prolonged activation of PARPs. This persistent activity consumes NAD⁺ (Johnson \u0026amp; Imai, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Demarest et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), a vital molecule required for DNA repair, mitophagy, sirtuin function, mitochondrial maintenance, and several key energy metabolism processes (Fang et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Johnson \u0026amp; Imai, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) thus inducing cellular senescence and inflammation which exacerbates age-related diseases (Poljsak \u0026amp; Milisav, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). During inflammatory response, CD38 which is predominantly expressed on immune cells is activated (Chini et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). The ageing process is associated with prolonged periods of inflammation which leads to increased CD38 activation, leading to a marked reduction in NAD⁺ levels within the cells, thus, reducing its activity (Hogan et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Targeting the biological processes of ageing, with the aim of promoting a longer period of healthy life are currently of interest (Schinaman et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). This is based upon the hypothesis that by slowing the ageing process itself, it may be possible to delay the occurrence and progression of chronic, age-related diseases (Kaeberlein et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eReports from several studies have shown that increasing the cellular levels of NAD⁺ has the potential to reduce the effects of ageing and delay the onset of age-related disorders (Houtkooper et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Trammell et al., \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Increasing NAD⁺ levels\u0026mdash;through intake of NAD\u003csup\u003e+\u003c/sup\u003e precursors and interventions like aerobic exercise, caloric restriction, and fasting\u0026mdash;has been shown to extend lifespan in animal models (Zhang et al., \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Yoshino et al., \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Burtscher et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Inhibitors of PARPs and CD38 activity are currently showing promise against several degenerative diseases like cancer, Diabetes, cardiovascular disease and ageing (Tarrag\u0026oacute; et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Li et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Hence there is a need to identify anti-ageing compounds with multifaceted inhibitory effect on these NAD\u003csup\u003e+\u003c/sup\u003e consumers.\u003c/p\u003e\u003cp\u003eMinocycline, formally known as 7-dimethylamino-6-desoxytetracycline, belongs to the second-generation tetracycline family and is an FDA-approved antibiotic (Yang et al., \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). It has been in use for more than three decades to combat, both Gram-positive and Gram-negative (Yun et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Minocycline has emerged as a promising therapeutic agent for neurological disorders, owing to its ability to penetrate the blood\u0026ndash;brain barrier. Experimental studies in animal models have consistently shown that it attenuates neuroinflammation and mitigates neuronal loss in several neurodegenerative diseases (Yun et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yang et al., \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAlthough some studies suggest that minocycline treatment in \u003cem\u003eDrosophila\u003c/em\u003e enhances FOXO activity\u0026mdash;a transcription factor downstream of insulin/TOR signaling and known to regulate stress responses and longevity across species\u0026mdash;important questions still remain (Lee et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Lim \u0026amp; Hyun, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Minocycline\u0026rsquo;s ability to extend lifespan in the w\u003csup\u003e1118\u003c/sup\u003e Drosophila strain, with impaired tryptophan transport (Lee et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2017\u003c/span\u003e),\u0026mdash; does not support the previously proposed hypothesis that its pro-longevity effects are mediated through the kynurenine pathway (Oxenkrug et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). However, it is possible that the minocycline-induced extension of lifespan in the w\u003csup\u003e1118\u003c/sup\u003e strain was through its supplementation of NAD\u003csup\u003e+\u003c/sup\u003e or through its ability to prevent depletion of NAD\u003csup\u003e+\u003c/sup\u003e with age. NAD⁺ is produced through multiple biosynthetic routes, including the Preiss\u0026ndash;Handler, salvage, and de novo pathways. In the de novo pathway, tryptophan is metabolized through the kynurenine pathway, ultimately generating NAD⁺ via the intermediate compound quinolinic acid (QA) (Cambronne \u0026amp; Kraus, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). This implies that the lifespan extension seen in the w\u003csup\u003e1118\u003c/sup\u003e strain, which has impaired intracellular tryptophan transport, could be due to the ability of minocycline to supplement levels of NAD\u003csup\u003e+\u003c/sup\u003e through the salvage pathway or its ability to inhibit NAD-consuming enzymes. However, this hypothesis remains to be tested.\u003c/p\u003e\u003cp\u003eComputational biology and bioinformatics offer efficient and cost-effective approaches for identifying and optimizing potential lead compounds (Onyango et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Hence, the present study screened minocycline and potent inhibitors against CD38 and PARP 2.\u003c/p\u003e"},{"header":"2.0 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Materials\u003c/h2\u003e\n \u003cp\u003eMost computational analyses were conducted on a system equipped with an Intel\u0026reg; Pentium\u0026reg; CPU B970 @ 2.30 GHz and 4 GB RAM, utilizing a range of software tools including PyMOL, PyRx, Discovery Studio, and Desmond. Additionally, various online databases and web servers\u0026mdash;such as PubChem, pkCSM, ProTox3, CASTp, PerMM, PASS, KEGG, and the Protein Data Bank (PDB)\u0026mdash;were employed for compound sourcing, prediction, and molecular analysis.\u003c/p\u003e\n \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\n \u003ch2\u003e2.1.1 Retrieval of the ligands\u003c/h2\u003e\n \u003cp\u003eThree-dimensional structures of minocycline (CID: 54675783), CD38 inhibitor 78c (CID: 118736856), and niraparib (CID: 24958200), which serve as standard inhibitors for CD38 and PARP2, were retrieved in Structure Data File (SDF) format from \u0026ldquo;the PubChem database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubchem.ncbi.nlm.nih.gov/\u003c/span\u003e\u003c/span\u003e)\u0026rdquo; (Marisa et al., \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n \u003ch2\u003e2.1.2 Retrieval of proteins\u003c/h2\u003e\n \u003cp\u003eThe 3D crystal structure of cyclic ADP ribose hydrolase (CD38) in complex with with a novel CD38-targeting antibody SAR650984 (PDB ID: 4CMH) with resolution of 1.53 \u0026Aring;, and poly(ADP-ribosyl)transferase-like 2 protein (PARP2) in complex inhibitor STO1542 (PDB ID: 4L7N) with 1.80 \u0026Aring; were downloaded from the \u0026ldquo;RCSB protein data bank (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.rcsb.org/\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e)\u0026rdquo;\u003c/span\u003e (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 ADMET and Druglikeness\u003c/h2\u003e\n \u003cp\u003eThe ADMET and drug-likeness profiles of minocycline, CD38 inhibitor 78c, and niraparib were evaluated using the \u0026quot;pkCSM web server (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://biosig.unimelb.edu.au/pkcsm/prediction)\u0026rdquo;(Marisa et al., 2021)\u003c/span\u003e\u003c/span\u003e. This tool predicts key pharmacokinetic parameters\u0026mdash;including Absorption, Distribution, Metabolism, Excretion, and Toxicity\u0026mdash;based on structural input. Lipinski\u0026rsquo;s Rule of Five was applied to assess drug-likeness (Chandel et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). Additional pharmacokinetic predictions included Caco-2 cell permeability, \u0026ldquo;intestinal absorption, skin permeability, volume of distribution (VDss), blood\u0026ndash;brain barrier and CNS permeability, cytochrome P450 inhibition profiles, total clearance, and hepatotoxicity\u0026rdquo; (Kumari \u0026amp; Dalal, \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). Parameters such as Caco-2 and skin permeability, along with P-glycoprotein interaction, were specifically used to assess drug absorption potential (Sivani et al., \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e). Metabolic profiling was based on cytochrome P450 (CYP) models to assess whether the compounds act as substrates or inhibitors of major CYP isoforms. Excretion parameters were estimated using total clearance values and renal OCT2 substrate prediction. Toxicological assessments included AMES mutagenicity, hERG channel inhibition, hepatotoxicity, and skin sensitization potential (Wahono et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e). Toxicity was also predicted by evaluating the carcinogenic, respiratory, nephrotoxic, cardiotoxic, neurotoxic, mutagenic, and cytotoxic effects of the drugs using \u0026ldquo;ProTox3 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://tox.charite.de/protox3/\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e)\u0026rdquo;\u003c/span\u003e (Banerjee et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e). Using the smiles of the compounds derived from the PubChem database, these parameters were calculated and compared against standard ranges (Quir\u0026oacute;s et al., \u003cspan class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Membrane Permeability\u003c/h2\u003e\n \u003cp\u003eThe membrane permeability of minocycline, the CD38 inhibitor 78c, and niraparib was evaluated using the \u0026ldquo;PerMM online tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://permm.phar.umich.edu/permm_server_cgopm)\u0026rdquo;(Wahono et al., 2024)\u003c/span\u003e\u003c/span\u003e, which predicts permeability coefficients, quantifies and aids the visualization of the translocation of compounds across lipid bilayer (Lomize et al., \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e). Depiction of translocation of the compounds was done using PyMOL (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pymol.org/2/\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e).\u003c/span\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e2.4 Preparation of Ligands and Protein\u003c/h2\u003e\n \u003cp\u003eThe 3D molecular structures of minocycline, CD38 inhibitor 78c, and niraparib were optimized through \u0026ldquo;energy minimization using the Universal Force Field (UFF) and the conjugate gradient algorithm\u0026rdquo;, executed over 200 iterations within PyRx-Python Prescription version 0.8 (Broni et al., \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e). Post-minimization, structures were converted to the pdbqt format using Open Babel (v2.3.1), incorporating the addition of hydrogen atoms, assignment of partial charges, and definition of rotatable bonds (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://openbabel.org/wiki/Main_Page\u003c/span\u003e\u003c/span\u003e) (Ogunyemi et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). Protein targets were \u0026ldquo;prepared using BIOVIA Discovery Studio Visualizer 2021 (v21.1) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://discover.3ds.com/discovery-studio-visualizer-download\u003c/span\u003e\u003c/span\u003e)\u0026rdquo;. During preparation, water molecules and non-essential heteroatoms were removed (Ravindranath et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). Polar hydrogens were added, and co-crystallized inhibitors were removed after identifying the active site. The final protein structures were saved in pdb format for molecular docking (Onyango et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e2.5 Binding Sites Prediction\u003c/h2\u003e\n \u003cp\u003e\u0026quot;The Computed Atlas of Surface Topography of Proteins (CASTp) server (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://sts.bioe.uic.edu/castp/calculation.html\u003c/span\u003e\u003c/span\u003e)\u0026rdquo; (Tian et al., \u003cspan class=\"CitationRef\"\u003e2018\u003c/span\u003e) was utilized to identify and evaluate the potential binding pocket of the CD38 protein, which lacked a co-crystallized ligand in its binding site (Bhat et al., \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e). For PARP2, the binding site was determined using site map generation in \u0026ldquo;BIOVIA Discovery Studio Visualizer 2021 (v21.1) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://discover.3ds.com/discovery-studio-visualizer-download\u003c/span\u003e\u003c/span\u003e)\u0026rdquo;, guided by the position of the co-crystallized ligand (Ruswanto et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e2.6 Molecular Docking\u003c/h2\u003e\n \u003cp\u003eUpon confirmation of favorable ADMET profiles, the prepared ligands were subjected to molecular docking with their respective target proteins using AutoDock Vina, integrated within the PyRx software. The target proteins were converted into pdbqt format, and docking grid boxes were defined based on the predicted binding sites (Onyango et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). For CD38, the grid box was centered at coordinates (24.6352, -19.1628, -13.1669), with dimensions (x\u0026thinsp;=\u0026thinsp;32.4267, y\u0026thinsp;=\u0026thinsp;32.5187, z\u0026thinsp;=\u0026thinsp;30.9969 \u0026Aring;). For PARP2, the grid center was set at (21.1174, -3.5739, 12.4086), with dimensions (x\u0026thinsp;=\u0026thinsp;30.0298, y\u0026thinsp;=\u0026thinsp;21.1835, z\u0026thinsp;=\u0026thinsp;23.6906 \u0026Aring;). The exhaustiveness parameter was increased to 8 to allow for broader conformational sampling. Docking results were assessed based on binding affinity scores, expressed in kcal/mol, where more negative values indicate stronger binding (Azmal et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e). The top-scoring conformations were saved in pdb format, and protein\u0026ndash;ligand interactions were analyzed using \u0026ldquo;BIOVIA Discovery Studio Client 2021 (v21.1) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://discover.3ds.com/discovery-studio-visualizer-download\u003c/span\u003e\u003c/span\u003e)\u0026rdquo; (Ruswanto et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e2.7 Visualization of Result\u003c/h2\u003e\n \u003cp\u003eBIOVIA Discovery Studio Client 2021 (v21.1) was used to examine the interaction profiles (2D and 3D) of the ligand\u0026ndash;protein complexes (Liu et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). This analysis focused on identifying critical binding features such as \u0026ldquo;hydrogen bonding, hydrophobic interactions, and other non-covalent forces to better understand the binding conformation and evaluate the interaction strength\u0026rdquo; between each ligand and its respective protein target (Azmal et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e). The output files, output.pdbqt, and macromolecule, were opened \u0026ldquo;Biovia Discovery Studio Visualizer 2021 (v21.1) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://discover.3ds.com/discovery-studio-visualizer-download\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e)\u0026rdquo;.\u003c/span\u003e During the docking process, only conformations with a RMSD of zero were considered, as these represent the most optimal binding poses (Azmal et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e). The binding affinities of minocycline were compared to those of the standard inhibitors for CD38 and PARP2. The top-ranked conformations, based on binding energy and interaction profile, were selected for subsequent molecular dynamics simulation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e2.8 Structure\u0026ndash;function Relationships (MD simulation)\u003c/h2\u003e\n \u003cp\u003eMolecular dynamics (MD) simulation is used in the exploration of the relationships between structure and function of macromolecules (Wahono et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e). The \u0026ldquo;Protein Preparation Wizard and Prime module in the Schr\u0026ouml;dinger Suite\u0026rdquo; was used to prepare the selected protein\u0026ndash;ligand complexes before MD simulation (Kumar et al., \u003cspan class=\"CitationRef\"\u003e2020\u003c/span\u003e). The steric clashes and strained geometries within the complexes were fixed through \u0026ldquo;restrained energy minimization, which allowed movement of heavy atoms up to 0.3 \u0026Aring;\u0026rdquo;. To evaluate the stability and dynamic behavior of the complexes, a 100-nanosecond molecular dynamics (MD) simulation was conducted using Desmond (Schr\u0026ouml;dinger, \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chandel et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). The complexes were optimized using standard fixed-charged force fields and solvation in transferable intermolecular potential with three points (TIP3P) water model and 0.15 M NaCl. Afterwards, energy minimization for 100 picoseconds (ps) was done prior to the run. MD simulation was then carried out at a temperature (300 K) using the NPT ensemble in an orthorhombic simulation box, with buffer dimensions of 10 \u0026times; 10 \u0026times; 10 \u0026Aring;\u0026sup3;. System energy (kcal/mol) was recorded at 1.2 picoseconds intervals throughout the simulation To ensure electrostatic neutrality, Na⁺ or Cl⁻ counterions were added to balance the net charge of the protein\u0026ndash;ligand complex (Chandel et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e). The stability and conformational dynamics of the simulated complexes were determined by assessing the RMSD, RMSF, solvent-accessible surface area (SASA), and radius of gyration (Rg) (Azmal et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e2.9 Potential Bioactivity Profiles\u003c/h2\u003e\n \u003cp\u003eTo evaluate the potential bioactivity of minocycline and the standard inhibitors, the \u0026ldquo;Prediction of Activity Spectra for Substances (PASS) online server (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.way2drug.com/passonline/predict.php\u003c/span\u003e\u003c/span\u003e)\u0026rdquo; (Alfarado \u003cem\u003eet al.\u003c/em\u003e). Through the generation of two parameters: \u0026ldquo;the probability of activity (Pa) and the probability of inactivity (Pi)\u0026rdquo;, this tool estimates the potential pharmacological effects of test compounds (Maity et al., \u003cspan class=\"CitationRef\"\u003e2025\u003c/span\u003e). This was done to further buttress the observations seen in literatures.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003e2.10 Analysis of Metabolic Pathway\u003c/h2\u003e\n \u003cp\u003e\u0026ldquo;Metabolic pathway analysis was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.genome.jp/kegg/pathway.html\u003c/span\u003e\u003c/span\u003e)\u0026rdquo; (Azmal et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003e2.11 Protein-protein interaction network analysis\u003c/h2\u003e\n \u003cp\u003eThe \u0026ldquo;STRING database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://string-db.org/\u003c/span\u003e\u003c/span\u003e) was used to determine protein\u0026ndash;protein interaction (PPI)\u0026rdquo; (Zhou et al., \u003cspan class=\"CitationRef\"\u003e2025\u003c/span\u003e) for CD38 and PARP2. The resulting PPI networks offer valuable insights into potential interacting protein residues that may modulate or be affected by inhibition of the target proteins (Azmal et al., \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3.0 Results","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e3.1 ADMET and druglikeness studies\u003c/h2\u003e\u003cp\u003eMinocycline and the standard inhibitors passed the rule of five (RoF) parameter with only minocycline failing the assumption of TPSA with TPSA\u0026thinsp;\u0026gt;\u0026thinsp;140, hence, depicting high druglikeness (Fig.\u0026nbsp;1A). Minocycline and the standard inhibitors all showed good to very good water solubility with values ranging from (\u0026lt;-2 to \u0026lt;-4). The result also revealed between moderate and high CaCo-2 permeability and intestinal absorption with minocycline having the least absorption in comparison with the standard inhibitors. With regard to skin permeability, minocycline and the standard inhibitors showed a constant skin permeability value of \u0026gt;\u0026thinsp;2.740. They were substrates of P-Glycoprotein. CD38 inhibitor 78c was predicted to be a P-glycoprotein I inhibitor while Niraparib was predicted to inhibit both P-glycoprotein I and P-glycoprotein II. We also observed a moderate (minocycline) to very high (standard inhibitors) distribution volume for all the compounds. For blood\u0026ndash;brain barrier membrane permeability, a logBB \u0026gt;-1 but \u0026lt;\u0026thinsp;0.3 in this study suggests that minocycline and the standard inhibitors poorly crossed the blood\u0026ndash;brain barrier. For CNS permeability minocycline and the standard inhibitors were predicted to poorly penetrate the CNS since (logPS \u0026lt;-2). minocycline and the standard inhibitors are not substrate of CYP2D6, but, CD38 inhibitor 78c and Niraparib are substrate of CYP3A4. Minocycline is not an inhibitor of any CYPs, however, CD38 inhibitor 78c inhibits CYP1A2, CYP2C19, CYP2C9 and CYP3A4 while Niraparib inhibits CYP1A2 and CYP2D6. They all showed high clearance value (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The results also suggest that minocycline and the standard inhibitors are not toxic in AMES test, however, CD38 inhibitor 78c and Niraparib are predicted to be hepatotoxic and neurotoxic. All compounds were predicted to cause respiratory toxicity, and only niraparib is predicted to have moderate carcinogenic risk (Fig.\u0026nbsp;1B).\u003c/p\u003e\u003cp\u003eTable 3 Computationally predicted values for Minocycline and the standard inhibitors (ADMET profile)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProperty\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eModel Name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMinocycline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCD38 inhibitor 78c\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNiraparib\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUnit\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLipinski rule of 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMolecular Weight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;500\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e457.483\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e413.543\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e320.396\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log g/mol)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLogP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.0481\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.5914\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (MLogP)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRotatable Bonds\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (RB)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAcceptors Hydrogen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (AH)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDonors Hydrogen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (DH)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMolar refractivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40\u0026ndash;130\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e119.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e118.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e97.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (MR)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTPSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e164.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e93.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e72.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (\u0026Aring;)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsorption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWater solubility\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026minus;10\u0026thinsp;\u0026lt;\u0026thinsp;poorly soluble\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026minus;6\u0026thinsp;\u0026lt;\u0026thinsp;moderately soluble\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026minus;4\u0026thinsp;\u0026lt;\u0026thinsp;soluble\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026minus;2\u0026thinsp;\u0026lt;\u0026thinsp;very soluble\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0\u0026thinsp;\u0026lt;\u0026thinsp;highly soluble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-3.118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-4.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-3.571\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log mol/L)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsorption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCaco2 permeability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.643\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.701\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.897\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log Papp in 10\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026nbsp;cm/s)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsorption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntestinal absorption (human)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow: 0\u0026ndash;20%\u003c/p\u003e\u003cp\u003eMedium: 20\u0026ndash;70%\u003c/p\u003e\u003cp\u003eHigh: 70\u0026ndash;100%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39.368\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e95.326\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e94.432\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (% Absorbed)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsorption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSkin Permeability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLikely skin permeable \u0026gt;-2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-2.741\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-2.758\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-2.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log Kp)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsorption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eP-glycoprotein substrate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsorption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eP-glycoprotein I inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbsorption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eP-glycoprotein II inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDistribution\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVDss (human)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow \u0026lt; -0.15\u003c/p\u003e\u003cp\u003eHigh\u0026thinsp;\u0026gt;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.429\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.512\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.861\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log L/kg)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDistribution\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFraction unbound (human)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.483\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.165\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.164\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (Fu)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDistribution\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBBB permeability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.3 (readily cross BBB)\u003c/p\u003e\u003cp\u003e\u0026lt;-1 (poorly cross BBB)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.592\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.029\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log BB)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDistribution\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCNS permeability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026gt;-2 (penetrate CNS)\u003c/p\u003e\u003cp\u003e\u0026lt;-3(cannot penetrate CNS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-3.613\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-2.367\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-2.126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log PS)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYP2D6 substrate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYP3A4 substrate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYP1A2 inhibitior\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYP2C19 inhibitior\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYP2C9 inhibitior\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYP2D6 inhibitior\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYP3A4 inhibitior\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExcretion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal Clearance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.263\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.569\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.868\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log ml/min/kg)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExcretion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRenal OCT2 substrate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAMES toxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMax. tolerated dose (human)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow\u0026thinsp;\u0026le;\u0026thinsp;0.477\u003c/p\u003e\u003cp\u003eHigh\u0026thinsp;\u0026gt;\u0026thinsp;0.477\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.127\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.575\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.138\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log mg/kg/day)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehERG I inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehERG II inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOral Rat Acute Toxicity (LD50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.397\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.449\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (mol/kg)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOral Rat Chronic Toxicity (LOAEL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.309\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.693\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.453\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log mg/kg bw/day)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepatotoxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSkin Sensitization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCategorical (Yes/No)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eT.Pyriformis\u0026nbsp;toxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eToxic: \u0026gt;-0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.285\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.438\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.745\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log ug/L)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMinnow toxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eToxic: \u0026gt;-0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.829\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.354\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.892\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNumeric (log mM)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eTPSA\u0026thinsp;=\u0026thinsp;Topological polar surface area, RB\u0026thinsp;=\u0026thinsp;Rotatable bond, AH\u0026thinsp;=\u0026thinsp;Acceptors Hydrogen, DH\u0026thinsp;=\u0026thinsp;Donor Hydrogen, and MR \u0026ndash; Molar refractivity\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003cp\u003e\u003cb\u003e3.2 Membrane Permeability Prediction\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003eFig 2A illustrates the conformational dynamics of minocycline and the standard inhibitors during their translocation across the cell membrane. Each compound adapted its orientation in response to the membrane\u0026rsquo;s hydrophilic and hydrophobic regions. Niraparib demonstrated the lowest membrane penetration energy, indicating more favorable translocation, whereas minocycline exhibited the highest energy, suggesting less efficient membrane permeability.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Binding site prediction\u003c/h2\u003e\u003cp\u003eIn this study, the binding pocket of 4CMH (CD38) had a surface area of 904.081 \u0026Aring;2 and a volume of 891.237 \u0026Aring;3 while that of 4L7N (PARP2) was 483.423 \u0026Aring;2 and 419.887 \u0026Aring;3 as predicted by the CASTP server. These pockets contained the following residues (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e),\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eArea and volume of binding pocket and residues within the pocket as predicted by CASTP server.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePDB ID (Protein)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArea (\u0026Aring;2)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVolume (\u0026Aring;3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eResidues\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4CMH (CD38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e904.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e891.237\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGLY 52, PRO 53, LEU 123, LEU 124, TRP 125, SER 126, ARG 127, LYS 129, LEU 145, GLU 146, ALA 154, ASP 155, ASP 156, LEU 157, THR 158, TRP 159, CYS 173, PRO 174, ASP 175, TRP 176, ARG 177, SER 181, ASN 182, ASN 183, PRO 184, VAL 185, SER 186, VAL 187, TRP 189, LYS 190, SER 193, PHE 196, ASP 217, ASP 219, SER 220, THR 221, PHE 222, GLU 226.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4L7N (PARP2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e483.423\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e419.887\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLYS 223, ILE 226, PHE 230, GLN 280, ASP 284, LEU 287, VAL 288, ALA 290, ASP 291, GLU 293, LEU 294, HIS 384, GLY 385,THR 386, ASN 387, VAL 390, ILE 394, LEU 399, ARG 400, ILE 401, MET 402, PRO 403, HIS 404, SER 405, GLY 406, GLY 407, ARG 408, GLY 410, LYS 411, GLY 412, ILE 413, TYR 414, PHE 415, ALA 416, LYS 421, SER 422, TYR 425, GLU 514.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Molecular docking\u003c/h2\u003e\u003cp\u003eIn the present study, we observed a slight increase in the binding affinity (lower binding energy (kcal/mol) of minocycline (-8.9 Kcal/mol) for CD38 in comparison with the binding affinity of the standard inhibitor CD38 inhibitor 78c (-8.4 Kcal/mol). Similarly, a slightly higher binding affinity was observed between minocycline (-10.2 Kcal/mol) and PARP2 in comparison with that of the standard inhibitor Niraparib (-10.1 Kcal/mol) (Fig.\u0026nbsp;3Ai and 3Aii). These values were derived from the best pose of the minocycline and the standard inhibitors within the binding pockets of CD38 and PARP2 (Fig.\u0026nbsp;3Bi and 3Bii)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Characterization of protein-ligand interaction\u003c/h2\u003e\u003cp\u003eInteraction mapping between target protein residues and the top-scoring ligands was performed to identify key intermolecular bonds involved in binding (Sivani et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Minocycline formed hydrogen bond interaction at THR221, SER186, GLU146, LEU157, and TYR414 and hydrophobic interaction at VAL185 and TRP125 with CD38 while CD38 inhibitor 78c formed hydrogen bond interaction at ASP156, TRP176, LYS190, PHE222, TRP125 and GLU226 and hydrophobic interaction with TRP125, TRP176 and TRP189 with CD38 at respective bond lengths (\u0026Aring;) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The result revealed no similarity in hydrogen bond interaction between minocycline and the standard inhibitor with CD38, however, both compounds had hydrophobic interaction with TRP125 of CD38. The interaction between minocycline and PARP2 was constituted of hydrogen bond at THR386, ASN387, TYR425 and TYR414 and hydrophobic interaction at TYR414 and TYR425. In addition, Niraparib formed hydrogen bond with PARP2 at ASP291 and PHE415 and hydrophobic bond at HIS384, TYR414, TYR425, LEU287, VAL288 and VAL390 at respective bond lengths (\u0026Aring;) as presented in (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). No similarity in hydrogen bond interaction between minocycline and the standard inhibitor with CD38 was seen, however, both compounds had hydrophobic interaction with PARP2 at TYR414 and TYR425. Figures\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eA\u0026ndash;D and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003eA\u0026ndash;D present the 2D and 3D interaction profiles between minocycline, the standard inhibitors, and the amino acid residues of CD38 and PARP2 for better interpretation.\u003c/p\u003e\u003cp\u003e\u003cimg 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\" width=\"452\" height=\"492\"\u003e\u003c/p\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Prediction of Potential Bioactivity\u003c/h2\u003e\u003cp\u003eOriginally classified as an antibiotic, minocycline also exhibits various biological activities beyond its antimicrobial properties. The results confirmed that most medium to high probability scores (Pa between 0.3 and 0.66) correlated with mechanisms underlying minocycline's antibiotic effects. Notably, minocycline was also predicted to influence NAD\u003csup\u003e+\u003c/sup\u003e levels and modulate the activity of CD38 and PARPs by inhibiting enzymes such as NAD\u003csup\u003e+\u003c/sup\u003e-dinitrogen-reductase ADP-D-ribosyltransferase, NAD(P)\u003csup\u003e+\u003c/sup\u003e-arginine ADP-ribosyltransferase, glutamate dehydrogenase, glutamate-5-semialdehyde dehydrogenase, protein tyrosine phosphatase, and cytokine release. However, these predictions indicated a weaker activity profile (Pa\u0026thinsp;\u0026lt;\u0026thinsp;0.3 but with Pa\u0026thinsp;\u0026gt;\u0026thinsp;Pi values). Similarly, Niraparib, aside from its role in inhibiting PARPs, showed potential for inhibiting NAD\u003csup\u003e+\u003c/sup\u003e-dinitrogen-reductase ADP-D-ribosyltransferase (Pa\u0026thinsp;=\u0026thinsp;0.26), glutamate-5-semialdehyde dehydrogenase (Pa\u0026thinsp;=\u0026thinsp;0.57), and protein tyrosine 2C phosphatase (Pa\u0026thinsp;=\u0026thinsp;0.07). In contrast to minocycline, CD38 inhibitor 78c appears to regulate NAD\u003csup\u003e+\u003c/sup\u003e levels by inhibiting coactivator-associated arginine methyltransferase 1 (Pa\u0026thinsp;=\u0026thinsp;0.142) and cyclin-dependent kinase (Pa\u0026thinsp;=\u0026thinsp;0.098) (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePredicted biological activity of minocycline and standard inhibitors of CD38 and PARPs\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCompound\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePa\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePi\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMinocycline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNAD+-dinitrogen-reductase ADP-D-ribosyltransferase inhibitor\u003c/p\u003e\u003cp\u003eNAD(P)+-arginine ADP-ribosyltransferase inhibitor\u003c/p\u003e\u003cp\u003eGlutamate dehydrogenase inhibitor\u003c/p\u003e\u003cp\u003eGlutamate-5-semialdehyde dehydrogenase inhibitor\u003c/p\u003e\u003cp\u003eProtein-tyrosine phosphatase inhibitor\u003c/p\u003e\u003cp\u003eCytokine release inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1930.219\u003c/p\u003e\u003cp\u003e0.169\u003c/p\u003e\u003cp\u003e0.294\u003c/p\u003e\u003cp\u003e0.171\u003c/p\u003e\u003cp\u003e0.097\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.029\u003c/p\u003e\u003cp\u003e0.192\u003c/p\u003e\u003cp\u003e0.026\u003c/p\u003e\u003cp\u003e0.176\u003c/p\u003e\u003cp\u003e0.033\u003c/p\u003e\u003cp\u003e0.051\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD38 inhibitor 78c\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCoactivator-associated arginine methyltransferase 1 inhibitor\u003c/p\u003e\u003cp\u003eCyclin-dependent kinase 6 inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1420.098\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003cp\u003e0.059\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNiraparib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNAD+-dinitrogen-reductase ADP-D-ribosyltransferase inhibitor\u003c/p\u003e\u003cp\u003eGlutamate-5-semialdehyde dehydrogenase inhibitor\u003c/p\u003e\u003cp\u003eProtein-tyrosine phosphatase 2C inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.263\u003c/p\u003e\u003cp\u003e0.571\u003c/p\u003e\u003cp\u003e0.065\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003cp\u003e0.046\u003c/p\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003e3.7 Metabolic pathway analysis\u003c/h2\u003e\u003cp\u003eFrom the Kegg database, CD38 is involved in nicotinate and nicotinamide metabolism, with matching proteins including SIRT4, SIRT1, NAMPT, NUDT12, NNT, BST1, NMNAT2, NMRK1, NMNAT1, NADK2, SIRT3, NAPRT, ENPP3, and NNMT. CD38 may modulate NAD\u003csup\u003e+\u003c/sup\u003e levels influencing various metabolic pathways, associated with the same set of proteins. Additionally, CD38 is expressed on hematopoietic cells impacting their differentiation and activation, with matching proteins including CD4, CD38, CD34, and CD19. It also indirectly affects riboflavin metabolism through the regulation of NAD\u003csup\u003e+\u003c/sup\u003e and related proteins such as ENPP3 and ENPP1. By maintaining NAD\u003csup\u003e+\u003c/sup\u003e homeostasis, CD38 influences pantothenate and CoA biosynthesis, also associated with ENPP3 and ENPP1. Furthermore, CD38 may contribute to cell adhesion processes via immune signaling modulation, again linked to proteins CD4, CD34, and PECAM1. Lastly, dysregulation of CD38 is associated with impaired immune responses contributing to primary immunodeficiency, with relevant proteins including CD4 and CD19. The result also revealed that PARP2 is involved in base excision repair, with matching proteins including PARP2, XRCC1, POLB, PARP1, and LIG3. PARP2 is also linked to apoptosis, associated with proteins PARP2, CASP3, and PARP1. Additionally, PARP2 plays a role in viral carcinogenesis, with relevant proteins POLB, CASP3, and H2BC11, indicating its potential involvement in the cellular response to viral infections and their ability to induce cancer (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cimg 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\" width=\"584\" height=\"366\"\u003e\u003c/p\u003e\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\u003ch2\u003e3.8 Analysis of Protein-protein interaction (PPI) Network\u003c/h2\u003e\u003cp\u003eProtein-protein interaction (PPI) network analysis conducted via the STRING database revealed significant functional associations involving CD38 and several key proteins, including SIRT1, SIRT3, NAMPT, ENPP1, NMNAT1, NMNAT2, CD19, CD3, CD4, and PECAM1. Notably, CD38 exhibited strong interaction with NAMPT, an enzyme critical for the conversion of nicotinamide to NMN, a precursor in the biosynthesis of NAD\u003csup\u003e+\u003c/sup\u003e. Furthermore, it showed interactions with SIRT1 and SIRT3, both of which are NAD\u003csup\u003e+\u003c/sup\u003e-dependent deacetylases (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). For PARPs, significant protein-protein interactions involving PARP2 and several critical proteins: H2AC6, HPF1, H2BC11, PARG, PARP1, POLB, LIG3, XRCC1, XRCC6, and CASP3 was observed. Notably, PARP2 demonstrated a strong interaction with PARP1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003eB).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003e3.9 Molecular Dynamics Simulation\u003c/h2\u003e\u003cp\u003eAll protein-ligand systems achieved structural stability, with protein backbone RMSD values falling within ranges typical of equilibrated globular proteins. For CD38, the average protein RMSD for the minocycline complex was lower with smaller fluctuations in comparison to the CD38 inhibitor 78C complex (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003eA and B). Similarly, for PARP2, the minocycline complex exhibited a lower average protein RMSD compared to the niraparib complex, with fluctuations within the same range in both systems (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003eC and D). Ligand RMSD and RMSF analyses consistently revealed that minocycline maintained more stable and rigid binding than either CD38 inhibitor 78C or niraparib. In the CD38 system, minocycline showed lesser ligand RMSD values and RMSF values in comparison to the CD38 inhibitor 78C which showed more variability in ligand RMSD and RMSF (Figs.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e \u0026amp; \u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e9\u003c/span\u003eA and B). Similarly, in the PARP2 system, minocycline exhibited lower RMSD and RMSF values in comparison to niraparib (Figs.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e \u0026amp; \u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e9\u003c/span\u003eC and D). For the protein-ligand interaction minocycline consistently formed more hydrogen bonds across both systems. Specifically, minocycline showed sustained interaction for over 70% of the simulation time with LYS 190. In contrast, CD38 inhibitor 78C and niraparib formed fewer hydrogen bonds, with more transient contacts spread across multiple residues. Although niraparib showed reduced number of hydrogen bonds, it revealed sustained interaction for over 70% of the simulation time with ARG 400 and GLU 514. Hydrophobic interactions were more pronounced in the standard inhibitors. Water bridges were observed in all systems but occurred more frequently in the minocycline complexes, enhancing their polar stabilization (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e10\u003c/span\u003eA-D). Torsional analyses showed that minocycline adopted more constrained bound conformations. Across its six rotatable bonds, minocycline's dihedral angles were narrowly distributed, while CD38 inhibitor 78C and niraparib, with seven and four rotatable bonds respectively, demonstrated broader torsional flexibility, reflecting greater conformational entropy (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e11\u003c/span\u003e). The radius of gyration (rGyr) remained stable across all ligands. Solvent exposure analysis showed higher SASA across both proteins (Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eChronic activation of CD38 and PARPs, particularly with advancing age, exacerbates NAD⁺ decline, impairing cellular activity and accelerating ageing-related pathologies. Thus, identifying compounds capable of modulating both targets could mitigate the ageing process through preservation of NAD\u003csup\u003e+\u003c/sup\u003e levels (Camacho-Pereira et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Covarrubias et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAn ideal oral drug should be absorbed, distributed, metabolized without losing its activity, excreted and without toxicity (Stielow et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). The pharmacokinetic and pharmacodynamic profiling of minocycline and the standard inhibitors (CD38 inhibitor 78c and Niraparib), revealed that they all demonstrated high drug-likeness potential, meeting RoF. However, minocycline was the only compound that exceeded the total polar surface area (TPSA) threshold (\u0026gt;\u0026thinsp;140), which can impact cell membrane permeability, potentially limiting its absorption (Matsson \u0026amp; Kihlberg, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Minocycline and the standard inhibitors displayed good to very good water solubility, with minocycline demonstrating lower absorption levels compared to standard inhibitors based on Caco-2 permeability and intestinal absorption predictions. In terms of skin permeability, minocycline and the standard inhibitors exhibited a consistent log Kp \u0026gt;-2.5, indicating limited skin permeability. This property may impact potential transdermal applications but is unlikely to affect the drug\u0026rsquo;s activity in oral administration. Distribution parameters highlighted significant variability among minocycline and the standard inhibitors. The distribution volume (VDss) for minocycline was moderate, whereas the standard inhibitors displayed very high distribution volumes, suggesting that the standard inhibitors may have broader tissue distribution. Blood-brain barrier permeability (logBB) was below 0.3 for minocycline and the standard inhibitors, indicating poor ability to cross the blood-brain barrier (Fong, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), which could limit central nervous system (CNS) side effects. CNS permeability, as indicated by logPS values \u0026lt; -2, suggested that minocycline and the standard inhibitors were poorly CNS-penetrant, a property that could be advantageous in reducing off-target CNS effects.\u003c/p\u003e\u003cp\u003eMinocycline, and the standard inhibitors, were identified as substrate of P-glycoprotein, a key transporter involved in cellular drug efflux (Sharom, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). CD38 inhibitor 78c inhibits P-glycoprotein I, whereas Niraparib was found to inhibit both P-glycoprotein I and II. These findings suggest that the inhibitors may differ in how they interact with drug transport pathways, potentially influencing their bioavailability and distribution within cells (Zhao et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Minocycline showed no inhibitory effects on CYP enzymes, suggesting a potentially lower risk of metabolic interactions, whereas CD38 inhibitor 78c and Niraparib were substrates and inhibitors of several CYP enzymes, including CYP1A2, CYP2C19, CYP2C9, and CYP3A4. These findings suggest a significant risk of drug-drug interactions, particularly in patients taking other medications metabolized by cytochrome P450 (CYP) enzymes. Minocycline and the standard inhibitors showed high clearance rates, which, together with their hydrophilic nature and molecular size, may support their efficient elimination from the body. According to AMES toxicity predictions, all compounds were classified as non-mutagenic. However, the standard inhibitors\u0026mdash;CD38 inhibitor 78c and Niraparib\u0026mdash;were associated with greater safety concerns, showing potential hepatotoxicity and neurotoxicity. Additionally, Niraparib presented a moderate risk for carcinogenicity. Despite these \u003cem\u003ein silico\u003c/em\u003e findings, further \u003cem\u003ein vivo\u003c/em\u003e research is essential to determine the dosage thresholds at which these compounds exert therapeutic benefits versus harmful effects.\u003c/p\u003e\u003cp\u003eMinocycline demonstrated a marginally higher binding affinity for both CD38 and PARP2 when compared to the standard inhibitors, suggesting its potential as a modulator of these NAD⁺-consuming enzymes. The increase in the binding affinity implies that minocycline may form stable interactions with the active sites of these proteins, potentially influencing their enzymatic activity. The possible inhibitory effect of minocycline on both CD38 and PARP2, two enzymes with central role in age-related NAD⁺ depletion, may have therapeutic relevance, particularly in ageing populations (Covarrubias et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Decline of intracellular NAD⁺ levels during ageing, have been associated with disruption in mitochondrial function, energy metabolism, and cellular repair mechanisms. By effectively interacting with these enzymes, minocycline may help preserve NAD⁺ availability, thereby supporting metabolic health and neuroprotection (Amjad et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). These observations are in line with prior studies, where pharmacological inhibition of CD38 using the CD38 inhibitor 78c led to improved metabolic outcomes and restored tissue NAD⁺ levels in aged mice (Tarrag\u0026oacute; et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Similarly, inhibition of PARP enzymes has been shown to confer neuroprotective benefits. Olaparib, a PARP inhibitor, reduced brain damage in a mouse model of transient cerebral ischemia (Teng et al., \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), while INO1001 mitigated neuronal degeneration in models of spinal cord injury and Huntington\u0026rsquo;s disease (Cardinale et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMinocycline formed hydrogen bonds at specific residues with CD38 (THR221, SER186, GLU146, LEU157, and TYR414) and exhibited hydrophobic interactions at VAL185 and TRP125, whereas the CD38 inhibitor 78c displayed hydrogen bonding at different residues and shared only the hydrophobic interaction at TRP125 with minocycline. A similar pattern was observed with PARP2, where minocycline and Niraparib shared hydrophobic interactions at TYR414 and TYR425 but exhibited different hydrogen bond interactions. These shared hydrophobic sites suggest that minocycline may mimic aspects of the binding behaviour of the standard inhibitors. Overall, this study suggests that minocycline could serve as a potential therapeutic strategy for counteracting NAD\u003csup\u003e+\u003c/sup\u003e depletion in ageing, though experimental validation is necessary to confirm these \u003cem\u003ein silico\u003c/em\u003e findings as well as assess the physiological relevance.\u003c/p\u003e\u003cp\u003eNiraparib, showed the lowest transfer energy, suggesting greater permeability across the lipid bilayer in comparison to minocycline and CD38 inhibitor 78c. This increased permeability provides Niraparib with access to the nuclear compartments where PARPs are located, thus, facilitating repair of the DNA (Vasil\u0026rsquo;eva et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Conversely, minocycline had the greatest transfer energy through the lipid bilayer, suggesting decreased permeabilities across membranes. The decrease in permeation of minocycline through the cell membrane implies that it may have appropriate inhibitory effect on the cell surface, where CD38 is mainly found (Shrimp et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). This makes minocycline a fine candidate for specific targeting of CD38. However, to target PARP2 within the nucleus, minocycline may require being in complex with transport proteins to ease cell entry (Vasil\u0026rsquo;eva et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePredicting the biological activity of minocycline and the standard inhibitors is essential in identifying their role in the regulation of the pathways associated with NAD\u003csup\u003e+\u003c/sup\u003e. Minocycline had a broad range of possible activities in comparison to the standard inhibitors. It is capable of binding to NAD\u003csup\u003e+\u003c/sup\u003e-dinitrogen-reductase ADP-D-ribosyltransferase and NAD(P)\u003csup\u003e+\u003c/sup\u003e-arginine ADP-ribosyltransferase, although, with less probabilities scores (Pa\u0026thinsp;\u0026lt;\u0026thinsp;0.3) indicating that it might influence levels of NAD\u003csup\u003e+\u003c/sup\u003e indirectly. This is consistent with the corresponding binding affinities against PARPs and CD38, and further contributes to the possibility of repurposing it in NAD\u003csup\u003e+\u003c/sup\u003e-linked drug treatment. Niraparib and CD38 inhibitor 78c, however, had more specific profile similar to their respective known drug targets. Niraparib, exhibited moderate ability to inhibit glutamate-5-semialdehyde dehydrogenase (Pa\u0026thinsp;=\u0026thinsp;0.57), which could suggest additional metabolic regulatory effect. In contrast, CD38 inhibitor 78c showed expected activity on enzymes coactivator-associated arginine methyltransferase 1, confirming its specificity for the modulation of CD38-involving NAD\u003csup\u003e+\u003c/sup\u003e pathways. The wider range of activity profile of minocycline may suggest that it has the potential to target many pathways of NAD\u003csup\u003e+\u003c/sup\u003e metabolism and as such can yield therapeutic benefits, particularly in overcoming the multifaceted age-related decrease in NAD\u003csup\u003e+\u003c/sup\u003e levels.\u003c/p\u003e\u003cp\u003eUsing the KEGG database valuable insights into the biological roles of the target proteins CD38 and PARP2 were further elucidated. CD38 was revealed to be involved in nicotinate and nicotinamide metabolism. It was also shown to interact with SIRT1, SIRT3, and NMNAT1, underscoring its central role in maintaining cellular levels of NAD\u003csup\u003e+\u003c/sup\u003e. PARP2 which is predominantly found in the nucleus, where it plays a pivotal role in base excision repair (Vasil\u0026rsquo;eva et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) was revealed to play a role in recruiting proteins like XRCC1 and POLB to sites of DNA damage using NAD\u003csup\u003e+\u003c/sup\u003e-dependent poly(ADP-ribosyl)ation. CD38\u0026rsquo;s was also shown to influence metabolic pathways with proteins such as ENPP1 and ENPP3, linking NAD\u003csup\u003e+\u003c/sup\u003e metabolism to riboflavin and pantothenate biosynthesis, suggesting that CD38 could have broad systemic impact. Similarly, PARP2 was associated with apoptosis and viral carcinogenesis, through CASP3 and H2BC11, underscoring its importance in maintaining genomic stability and cellular response to stress. PARP2 also interacted with XRCC1 and LIG3 further supporting its role in the base excision repair pathway (Lee \u0026amp; Lee, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Additionally, its interaction with HPF1 a protein essential for enhancing the specificity of ADP-ribosylation by PARPs, further influences NAD\u003csup\u003e+\u003c/sup\u003e utilization. The interaction of PARP2 with histones (H2AC6 and H2BC11) suggests its role in changing chromatin structure, a fundamental component of DNA repair and transcriptional regulation.\u003c/p\u003e\u003cp\u003eThe PPI network analysis further buttresses report from the KEGG database. CD38 interacted with NAMPT, SIRT1, and SIRT3, further supporting its pivotal role in regulating NAD\u003csup\u003e+\u003c/sup\u003e levels and linking metabolism to immune signaling pathways (Yang et al., \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). This suggests that in ageing and age-related diseases where CD38 is upregulated and NAD\u003csup\u003e+\u003c/sup\u003e levels are compromised, targeting CD38 could influence both metabolic homeostasis and immune cell function. PARP2 also interacted with PARP1, XRCC1, and LIG3 emphasizing its critical role in the DNA damage response and base excision repair which consume NAD\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe analysis of protein-ligand interactions revealed that minocycline had lower RMSD and RMSF values, suggestive of a more stable complex with both CD38 and PARP2. This suggest that minocycline may offer more sustained inhibition (Ogunyemi et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) of NAD\u003csup\u003e+\u003c/sup\u003e-consuming enzymes, and may have significant implications for the treatment of age-related diseases associated with NAD\u003csup\u003e+\u003c/sup\u003e decline (Covarrubias et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Minocycline formed more hydrogen bonds and water bridges which are crucial for stabilizing the protein-ligand complex and ensuring effective target interaction (Chen et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) in comparison to CD38 inhibitor 78C and niraparib, with more lesser interactions. Increased stability of minocycline in this study in comparison to the standard inhibitors suggests that minocycline could provide more consistent and durable inhibition of CD38 and PARP2, thereby potentially preserving cellular level of NAD\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePrevious studies have associated the higher stability and polarity of minocycline to its significant ability to cross the blood-brain barrier, (Yun et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Asadi et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), although contrasting with observations in this study, where reduced permeation through the blood brain barrier was seen. The torsional analysis indicated that minocycline had a more constrained conformation compared to the standard inhibitors, with greater flexibility in their binding modes. This reduced conformational change suggests that minocycline may exert more stable and predictable effects, improving the feasibility of its use for long-term.\u003c/p\u003e\u003cp\u003eThe solvent-accessible surface area (SASA) defined by the van der Waals contact surface of the protein and the center of the hypothetical solvent sphere provides insight into how exposed a ligand is to the surrounding solvent while bound to its target (Ogunyemi et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Higher SASA values typically suggest that more of the ligand\u0026rsquo;s surface is in contact with the aqueous environment. In contrast, lower SASA values indicate that a greater portion of the ligand is buried within the protein\u0026rsquo;s binding pocket, which often correlates with stronger hydrophobic interactions (Marsh \u0026amp; Teichmann, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Metin \u0026amp; Kawano, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). The increased SASA observed in the minocycline-CD38 and minocycline-PARP2 complexes suggests that minocycline had both binding pockets exposed to solvent. In developing anti-aging drugs, where modulation rather than full inhibition of enzymes like CD38 and PARP2 might be preferable, minocycline\u0026rsquo;s partially solvent-exposed conformation may create an equilibrium between efficacy and safety. Hence, its desirability for long-term interventions. The radius of gyration evaluates the structural compactness of protein\u0026ndash;ligand complexes throughout the simulation (Ogunyemi et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). The radius of gyration remained stable for minocycline and the standard inhibitors demonstrating their stability and compactness.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the findings from this study suggest that minocycline may possess therapeutic effects in the regulation of NAD\u003csup\u003e+\u003c/sup\u003e metabolism. Its stable binding to NAD\u003csup\u003e+\u003c/sup\u003e-consuming enzymes (CD38 and PARP2), suggest that it may preserve NAD\u003csup\u003e+\u003c/sup\u003e levels which decline with age, hence, could slow down ageing and the onset of age-related diseases. Further \u003cem\u003ein vivo\u003c/em\u003e studies, are required to validate these findings and to evaluate the long-term impact of minocycline on NAD⁺ homeostasis and the ageing process. If validated, minocycline may emerge as a versatile therapeutic candidate, targeting critical ageing pathways and potentially enhancing healthspan while mitigating age-associated deterioration.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research was partly funded by the Institution Based Research grant by Tetfund (REF: TETF/DR\u0026amp;D/UNI/ZARIA/IBR/2020/VOL.1/53)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll datasets analyzed during this study are included within the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest related to the research, authorship, or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOluwasegun Davis Olatomide (ODO), Sunday Abraham Musa (SAM), and Amos Olalekan Abolaji (AOA) were responsible for conceptualization and design of the study. ODO, Zainab Mahmood Bauchi (ZMB), Sohnap James Sambo (SJS), Abel Nosereme Agbon (ANA), wrote and edited the manuscript. ODO and Akinyemi Ademola Omoniyi (AAO) performed the data curation and analysis. SAM and AOA reviewed and edited the final version of the manuscript. All authors read and approved the final manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAlfarado, D., Shiyan, S., \u0026amp; Ferlinahayati, F. Study of Potential \u0026Alpha;-Glucosidase Inhibitor from Tithonia Diversifolia: In Vitro, Pharmacokinetics, Toxicology, and Molecular Docking. \u003cem\u003eIndonesian Journal of Chemistry\u003c/em\u003e.\u003c/li\u003e\n\u003cli\u003eAmjad, S., Nisar, S., Bhat, A. A., Shah, A. R., Frenneaux, M. P., Fakhro, K., Haris, M., Reddy, R., Patay, Z., \u0026amp; Baur, J. (2021). 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Pan-Cancer Profiling of Fzd2 as a Prognostic Biomarker: Integrative Multi-Omics Analysis with Experimental Validation and Functional Characterization in Gastric Cancer. \u003cem\u003eFrontiers in Pharmacology, 16\u003c/em\u003e, 1534974.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"58cb0f11-c549-4b64-9ef7-74ef7ba0e7e7","identifier":"10.13039/501100008895","name":"Tertiary Education Trust Fund","awardNumber":"TETF/DR\u0026D/UNI/ZARIA/IBR/2020/VOL.1/53","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Ahmadu Bello University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Minocycline, CD38, PARP2, drug repurposing, ageing, NAD⁺ consumers","lastPublishedDoi":"10.21203/rs.3.rs-7474241/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7474241/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChronic activation of enzymes that require NAD⁺ for their activity such as CD38 and PARPs accelerates its decline with age, impairing cellular metabolism and contributing to degenerative processes. Targeting these enzymes may help preserve NAD⁺ levels and delay ageing-related pathologies. This study investigated the potential inhibitory activity of minocycline against CD38 and PARP2 using \u003cem\u003ein silico\u003c/em\u003e approaches. Structures of minocycline and standard inhibitors for CD38 and PARPs were obtained from PubChem, while protein structures were retrieved from the Protein Data Bank (PDB). The ligands were docked against the protein using PyRx, and ligand-protein interactions were visualized with Discovery Studio Visualizer. Pharmacokinetic properties were assessed via pkCSM, toxicity was predicted using ProTox, and membrane permeability evaluated using PerMM. Ligands with favourable docking scores were further subjected to molecular dynamics (MD) simulations over a 100 ns trajectory. Minocycline demonstrated higher binding affinity for CD38 (\u0026minus;\u0026thinsp;8.9 kcal/mol) and PARP2 (\u0026minus;\u0026thinsp;10.2 kcal/mol) compared to their respective standard inhibitors (\u0026minus;\u0026thinsp;8.4 and \u0026minus;\u0026thinsp;10.1 kcal/mol). MD simulations revealed that minocycline formed more stable complexes with both targets, as indicated by lower root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values. Radius of gyration analysis confirmed compact and stable protein-ligand complexes. These results suggest that minocycline may inhibit NAD⁺ consumers more effectively than existing inhibitors, potentially preserving NAD⁺ levels and mitigating the ageing process. The findings support the rationale for repurposing minocycline as a multi-target anti-ageing therapeutic.\u003c/p\u003e","manuscriptTitle":"Targeting Age-Associated NAD⁺ Decline: in silico Evaluation of Minocycline as an Inhibitor of CD38 and PARP2","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-29 05:37:58","doi":"10.21203/rs.3.rs-7474241/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"df017dc9-4adc-4475-aedd-dd54af4cc432","owner":[],"postedDate":"August 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53809197,"name":"Computational Biology"},{"id":53809198,"name":"Drug Discovery, Design, \u0026 Development"}],"tags":[],"updatedAt":"2026-04-26T13:39:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-29 05:37:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7474241","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7474241","identity":"rs-7474241","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}