AbstractBackgroundAlzheimer's disease (AD) is an age‐associated, progressive neurodegenerative disease characterized by decline in cognitive function. There is presently no cure for AD and the currently used drugs have limited efficacy. Cholinergic enzyme inhibition, oxidative stress and neuroinflammation have been growing areas of research in the pharmacological management of AD (Simunkova et al., 2019). Furthermore, computational approaches have been instrumental in designing and discovering new drugs for several diseases (Romano & Tatonetti, 2018). Solanum macrocarpon L. (eggplant) is a specie of African ancestry reported to be an ethno‐ medicinal plant that improves memory (Ogunsuyi et al., 2018). This study therefore investigated the antioxidant and acetylcholinesterase (AChE) inhibitory potential of S. macrocarpon leaf extracts, identified active compound(s) and explored their enzyme‐ligand interactions using In silico approaches to discover new functional leads for AD.MethodMethanol extract and fractions of S. macrocarpon leaves were subjected to phytochemical investigation of AChE inhibitory activity and cell‐free antioxidant activity. Phytochemicals were identified through the profiling of the most potent fraction using Liquid Chromatography‐Mass Spectrometry (LC‐MS) and Gas Chromatography‐Mass Spectrometry (GC‐MS). Molecular docking was performed employing AutoDock Vina. The prediction of the ADMET properties was obtained using pkCSM and SwissADME online tools. Furthermore, the compound(s) with favorable pharmacokinetic properties and interaction with key residues within the AChE active site was selected for molecular dynamics (MD) simulation studies using GROMACS 5.0.7.ResultThe S. macrocarpon leaves ethyl‐acetate fraction (SMEA) displayed the highest concentration‐dependent inhibition of AChE and highest antioxidant capacity among the fractions. Seventy‐eight (78) and sixty (60) compounds were tentatively identified from the LC‐MS and GC‐MS of SMEA respectively. A total number of 21 compounds demonstrated better docking score than the standard, eserine and interacted with key residues within the human acetylcholinesterase (PDB ID:4EY7) active site akin to Donepezil. Amongst the compounds with the least docking score, 1,1‐Biphenyl‐4‐carboxylic acid showed the most favorable pharmacokinetic properties. Also, the 10ns MD produced a trajectory which showed stable Root‐Mean‐Square‐Deviation and favorable g_mmpbsa energy calculations.ConclusionThe current study proposes that 1,1‐Biphenyl‐4‐carboxylic acid, a constituent of S. macrocarpon is a potential lead compound for AD management.