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

• Published in: Journal of computer-aided molecular design 2020-09, Vol.34 (9), p.983-1002
• Main Authors: Tripathi, Manish Kumar, Sharma, Piyoosh, Tripathi, Avanish, Tripathi, Prabhash Nath, Srivastava, Pavan, Seth, Ankit, Shrivastava, Sushant Kumar
• Format: Article
• Language: English
• Subjects: Animal Anatomy; Biological activity; Chemistry; Chemistry and Materials Science; Cholinesterase; Computer Applications in Chemistry; Computer simulation; Dynamic stability; Enzyme kinetics; Histology; Molecular docking; Molecular dynamics; Morphology; Pathogenesis; Physical Chemistry; Simulation analysis; Stability analysis
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-020-00318-w

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, IC 50  = 0.062 µM; BChE, IC 50  = 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.