Virtual screening of lead compounds for the treatment of Alzheimer's disease based on multi-target strategy

作者全名："Li, Ruo-yu; Xie, Jia-li; Meng, Dan; Deng, Ping"

作者地址："[Li, Ruo-yu; Xie, Jia-li; Meng, Dan; Deng, Ping] Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China; [Li, Ruo-yu; Xie, Jia-li; Meng, Dan; Deng, Ping] Chongqing Res Ctr Pharmaceut Engn, Chongqing, Peoples R China; [Deng, Ping] Chongqing Key Res Lab Qual Evaluat & Safety Res A, Chongqing, Peoples R China"

通信作者："Deng, P (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China.; Deng, P (通讯作者)，Chongqing Res Ctr Pharmaceut Engn, Chongqing, Peoples R China.; Deng, P (通讯作者)，Chongqing Key Res Lab Qual Evaluat & Safety Res A, Chongqing, Peoples R China."

来源：MOLECULAR SIMULATION

ESI学科分类：CHEMISTRY

WOS号：WOS:000832515700001

JCR分区：Q3

影响因子：2.1

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Alzheimer's disease; acetylcholinesterase inhibitors; virtual screening; multi-target medicines; molecular dynamics simulation

摘要："Alzheimer's disease (AD) is a neurological illness that develops over time. Although the disease's origin and pathophysiology remain unclear, acetylcholinesterase (AChE) has been identified as a potential target. Other targets including glycogen synthase kinase 3 beta (GSK-3 beta), beta-secretase (BACE-1), and others, are also being investigated as possible therapeutic targets. In this work, compounds from the DrugBank and ZINC subset drug-like databases were screened in silico using ligand-based pharmacophore filtering and molecular docking. Two multi-target compounds, ZINC-27 and ZINC-1-4, were discovered utilising a combination of compound profiling, ADMET prediction, and structural modification, which can inhibit AChE, GSK-3 beta, and BACE-1. Finally, the trustworthiness of the virtual screening findings was confirmed using molecular dynamics simulation, MM-PBSA binding free energy calculation, and principal component analysis. In conclusion, the multi-approach study revealed that ZINC-27 and ZINC-1-4 might be prospective multi-target anti-AD medicines that work concurrently on AChE, GSK-3 beta, and BACE-1, which merit further investigation."

基金机构：Natural Science Foundation of Chongqing [cstc2019jcyj-msxmX0034]

基金资助正文：This research was supported by the Natural Science Foundation of Chongqing [grant number: cstc2019jcyj-msxmX0034].