Development of Pyrazole Harbouring Novel Leads Against β-Amyloid Protein Fibrillation by in silico Drug Design

Author:

Mishra Puja1,Biswas Sujata1,Baur Sudipta1,Basak Souvik1,Mukherjee Arup2,Basu Anindya3

Affiliation:

1. Dr. B. C. Roy College of Pharmacy & Allied Health Sciences, Durgapur, WB, India

2. Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, WB, India

3. School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India

Abstract

Amyloid [Formula: see text] (A[Formula: see text]) peptide monomers polymerize to form insoluble amyloid fibril aggregates and accumulate as senile plaques which eventually leads to cognitive impairment. Modulating abnormal amyloid aggregation can be considered a therapeutic target for Alzheimer’s disease. Recent studies support that Curcumin interferes with larger protein aggregate formation by destabilizing the salt bridge (Asp 23-Lys 28) of A[Formula: see text] protein. The chemical library of curcumin derivative with pyrazole, isoxazole, and isothiazole showed considerable binding affinity comparable to that of curcumin. In silico docking studies of the library of the compound, revealed strong binding affinity with A[Formula: see text] protein and [Formula: see text]-secretase enzyme (BACE1). De novo ligand design coupled with manual pharmacophore mapping of our best-fitting lead revealed another ligand having a potential binding affinity with both A[Formula: see text] protein and BACE-1. Both the compounds passed Lipinski’s Rule of Five, in silico toxicity testing by admetSAR, and pharmacophore overlaps with Verubecestat, a compound under clinical trial against Alzheimer’s disease. MD dynamic simulation study revealed the stability of protein after it binds to our ligand. Secondary structure determination was also done to observe the changes in [Formula: see text] and [Formula: see text] sheets of the protein with and without ligand binding. Ligand-based drug design was also carried out via pharmacophore mapping and searching the molecules via zinc database.

Publisher

World Scientific Pub Co Pte Ltd

Subject

Computational Theory and Mathematics,Physical and Theoretical Chemistry,Computer Science Applications

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3