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Alzheimer's disease (AD) is a form of Dementia known to diminish the brain's function by perturbating its structural and functional components. Though cholinesterase inhibitors are widely used to treat AD, they are limited by numbers and side effects. Hence, present study aims to identify structurally diverse Acetylcholinesterase (AChE) inhibitory plant secondary metabolites (PSM) by employing high throughput screening and computational studies. AChE inhibitory activity was performed using 390 crude extracts from 63 plant parts belongs to 58 plants. The lowest IC 50  value was recorded by acetone extract of  Cyperus rotundus  rhizome at 0.5 mg/ml, followed by methanol extract of  Terminalia arjuna  bark (0.95 mg/ml) and water extract  Acacia catechu  stem (0.95 mg/ml). A virtual library containing 487 PSM belongs to 18 plants found positive for AChE inhibition (IC 50 ≤5 mg/ml) was prepared. Through ADMET analysis, 78 PSM fulfilling selected drug-likeness parameters were selected for further analysis. Molecular docking studies of selected PSM against AChE recorded a wide range of binding energy from −3.40 to −10.90 Kcal/mol. Further molecular dynamics simulation studies also recorded stabilized interactions of AChE-ligand complexes in the term of RMSD, RMSF, Rg, SASA, and hydrogen bond interaction. MMPBSA analysis revealed the binding energy of selected PSM ranging from −123.757 to −261.697 kJ/mol. Our study demonstrated the potential of 12 PSM (Sugiol, Margolone, 7-Hydroxy-3',4’-(Methylenedioxy) flavan, Beta-cyprone, Ethenone, Isomargolonone, Serpentine, Cryptolepine, Rotundone, Strictamin, Rotundenol and Nootkatone) as AChE inhibitors. Further  in vitro  and  in vivo  experimental evaluations with pure PSM could be beneficial for therapeutic uses.

A combinatorial approach to screen structurally diverse acetylcholinesterase inhibitory plant secondary metabolites targeting Alzheimer’s disease