Computational Analysis of Fluoxetine, Gabapentin and Simvastatin ZINC Analogues for Neurogenesis Induction Activity in Ischemic Stroke

Abstract

Stroke causes substantial mortality and disability, and current treatments leave a need for approaches supporting brain repair. Neurogenesis-related pathways provide potential targets, but the activity and safety of candidate compounds require rigorous evaluation using complementary computational and experimental approaches. This study compared fluoxetine, gabapentin and simvastatin with selected ZINC analogues to prioritise compounds for experimental investigation of neurogenesis-related activity after ischaemic stroke.This in-silico study combined ligand-based screening, molecular docking, pharmacokinetic prediction and toxicity prediction. SwissSimilarity identified 233 fluoxetine analogues and 400 analogues each for gabapentin and simvastatin. ZINCPharmer provided 18 additional gabapentin candidates. Ligands were prepared and optimised before AutoDock Vina docking against the serotonin 1A receptor (5-HT1A), serotonin transporter (SERT), voltage-gated calcium-channel auxiliary subunit α2δ2, and peroxisome proliferator-activated receptor alpha (PPAR-α), with parent drugs as comparators. Two docking runs per ligand–target pair used exhaustiveness 8. SwissADME and ProTox-III predicted pharmacokinetic and toxicological profiles.ZINC000012922723 produced more favourable docking scores than fluoxetine at both 5 HT1A and SERT. ZINC000005029316 and ZINC67903067 achieved scores of −8.2 kcal/mol at α2δ2. ZINC000096085336 had the most favourable simvastatin-series docking score, although interaction patterns
required binding-site verification. Fluoxetine analogues showed favourable predicted absorption and brain permeability but frequent CYP inhibition flags. Gabapentin analogues varied in predicted permeability and synthetic accessibility. Toxicity flags across the series prevented conclusions of overall safety.ZINC000012922723 and ZINC000005029316 are priority candidates for experimental evaluation based on the combined computational results. Docking and predicted disposition do not establish neurogenic efficacy or safety. Target-specific docking validation, functional assays and experimental pharmacokinetic and toxicity studies are needed before therapeutic conclusions can be drawn.