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Combinatorial Chemistry & High Throughput Screening

Author(s): Richa Arya*, Sarvesh Paliwal, Satya P. Gupta, Swapnil Sharma, Kirtika Madan, Achal Mishra, Kanika Verma and Neha Chauhan

DOI: 10.2174/1386207323999200918151331

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In-silico Studies and Biological Activity of Potential BACE-1 Inhibitors

Page: [729 - 736] Pages: 8

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Abstract

Background: Alzheimer’s disease is a neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in the brain are caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP).

Objective: The controlled APP processing by inhibition of secretase is the strategy to reduce Aβ load to treat Alzheimer’s disease.

Methods: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with an activity magnitude greater than 4 of compounds.

Results: In the advent of designing new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by the in-silico approach were evaluated by docking interactions.

Conclusion: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl-substituted carbamate compound exhibited the highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1μM.

Keywords: BACE-1, docking, in-silico, pharmacophore, secretase, secretase, BACE-1.

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