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

Abstract

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 IC₅₀ 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 (IC₅₀≤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.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Secondary metabolite
• cholinesterase inhibitor
• molecular docking
• MMPBSA
• drug-likeness

Acknowledgements

The authors are grateful to Dr. Sampat Kumar, Assistant Professor, Department of Botany, University of Davengare, Karnataka, India, for helping with plant identification. HP thanks IIT Delhi for providing the FIRP grant, and GC thanks ICMR for financial support. HP, SS, and GC also thank the HPC-facility at IIT-Delhi.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contribution

Conceptualization Hariprasad P.; Data curation Gourav Choudhir; Formal analysis Gourav Choudhir and Hariprasad P.; Investigation Gourav Choudhir; Methodology Gourav Choudhir and Hariprasad P.; Project administration Hariprasad P.; Resources Hariprasad P. and Satyawati Sharma; Software Open access; Supervision Hariprasad P. and Satyawati Sharma; The manuscript was written through contributions of all authors. All authors have approved the final version of the manuscript.