Richa Arya1, Sarvesh Paliwal1, Satya P Gupta2, Swapnil Sharma1, Kirtika Madan1, Achal Mishra3, Kanika Verma1, Neha Chauhan1.
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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
Entities:
Keywords:
BACE-1; docking; in-silico; pharmacophore; secretase
Year: 2021
PMID： 32957879 DOI： 10.2174/1386207323999200918151331
Source DB: PubMed Journal: Comb Chem High Throughput Screen ISSN： 1386-2073 Impact factor: 1.339