Computational exploration and experimental validation to identify a dual inhibitor of cholinesterase and amyloid-beta for the treatment of Alzheimer's disease.

Authors

Manish Kumar Tripathi, Piyoosh Sharma, Avanish Tripathi, Prabhash Nath Tripathi, Pavan Srivastava, Ankit Seth, Sushant Kumar Shrivastava

Published in

Journal of computer-aided molecular design. Volume 34. Issue 9. Pages 983-1002. Epub Jun 03, 2020.

Abstract

The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC₅₀ = 0.062 µM; BChE, IC₅₀ = 1.482 µM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Aβ aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines.

PMID:
32488355
Bibliographic data and abstract were imported from PubMed on 13 Nov 2026.

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