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In‐silico and in‐vitro evaluation of imidazolone fused quinazolinone derivatives as anti‐amyloidal agents in Alzheimer’s
Author(s) -
Sharma Lalit,
Kumar Deepak,
Bisht Gopal Singh
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.038321
Subject(s) - chemistry , in vitro , docking (animal) , in silico , biochemistry , amyloid (mycology) , pharmacology , biology , medicine , inorganic chemistry , nursing , gene
Background Alzheimer’s disease with a long preclinical period of ∼20 years is a chronic, insidious, and progressive neurodegenerative disease of old age. Neuropathologically AD is characterized by the presence of accumulated Amyloid‐beta in plaques (in extracellular spaces, and walls of blood vessels) and aggregated tau protein in neurofibrillary tangles. Quinazolinone derivatives exhibit inhibition to β‐secretase as well as its core quinazoline moiety prevents the cholinergic system from pathological activities of Aβ by possessing significant amount of inhibition. Method In‐silico evaluation was based over computational approaches counting receptor and ligand preparation, grid formation, docking simulation, and its analysis followed by in‐vitro investigation via Thioflavin T‐amyloid binding assay and Protease (Trypsin) digestion assay. Result The computational approach provides us with two molecules A and B with higher estimated free energy of binding whereas for the justification of in‐vitro test results one molecule J with lower estimated free energy of binding from top ten docked scored molecules was selected. In‐vitro investigation of these three compounds reveals that compound A cause significant (p<0.005) reduction in fluorescence intensity of ThT as well as Aβ 1‐42 peptides resistance to tryptic digestion, when compared with control. Compound B possess lesser amount of reduction (p<0.005) in both the assays as compared to compound A whereas, activity of Compound J was found to be almost negligible. Conclusion From the present study we found that our test compound A has shown significant results in modulating the Aβ aggregates i.e. Aβ fibrils. This study strongly suggests the further evaluation of this imidazolone fused quinazolinone derivative.