Akinduko_2026_In.Silico.Pharmacol_14_64

Ficus capensis (FC) and Parquetina nigrescens (PN) are traditional African medicinal plants with reported neuropharmacological properties, yet their active compounds and mechanisms remain poorly characterized. This study employed an integrative experimental and computational strategy to compare their phytochemical profiles and neuroprotective mechanisms, aiming to identify multi-target therapeutic candidates. Phytochemical constituents were profiled using HPLC and GC, while in vitro neuroprotective effects were evaluated through cholinesterase inhibition and lipid peroxidation (LPO) assays. Network pharmacology, Gene Ontology, KEGG enrichment, molecular docking, and molecular dynamics (MD) simulations were conducted to uncover mechanistic pathways and prioritize key compounds. The top-performing FC ethanolic extract (FCET) and its major bioactive, luteolin, were further tested for HDAC1 inhibition and thermal target engagement. FC showed a richer neuroactive phytochemical profile than PN, and exhibited stronger inhibitory effects on acetylcholinesterase, butyrylcholinesterase, and LPO. Network pharmacology identified 304 neurodegeneration-related protein targets, highlighting AKT1, HDAC1, EP300, STAT3, and EGFR as core nodes, enriched in MAPK, PI3K-AKT, and Ras pathways. Luteolin ranked highest across these targets, outperforming native ligands in docking scores. MD simulations confirmed the stability of luteolin-target interactions, with RMSD values < 0.3 nm and minimal structural fluctuations. Luteolin and FCET also showed potent HDAC1 inhibition, confirmed by IC(50) values and significant thermal stabilization (deltaTm). These findings position Ficus capensis as a promising neuroprotective agent and luteolin as a viable multi-target lead compound. The study offers mechanistic insight into their therapeutic potential and supports further development of FC-derived agents for neurodegenerative disease intervention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00557-z.