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.
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Acknowledgments
The authors gratefully acknowledge to Indian Institute of Technology (BHU) for providing financial assistance through postdoctoral fellowship (Grant No. PDF/007/15-16/16-17). The authors are also thankful to the Department of Health Research, Ministry of Health and Family Welfare for providing the Young Scientist Project in newer areas of Drugs Chemistry (DHR/HRD/YS-15-2015-16).
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Tripathi, M.K., Sharma, P., Tripathi, A. et al. Computational exploration and experimental validation to identify a dual inhibitor of cholinesterase and amyloid-beta for the treatment of Alzheimer’s disease. J Comput Aided Mol Des 34, 983–1002 (2020). https://doi.org/10.1007/s10822-020-00318-w
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DOI: https://doi.org/10.1007/s10822-020-00318-w