阿尔茨海默病I、IIb类组蛋白去乙酰化酶抑制剂的鉴定。

PubMed ID
发表日期 2020年Sep月

原始出处 生命科学
Life sciences
作者 Gupta  Rohan  Ambasta  Rashmi K  Kumar  Pravir 

文献标题 阿尔茨海默病I、IIb类组蛋白去乙酰化酶抑制剂的鉴定。
Identification of novel class I and class IIb histone deacetylase inhibitor for Alzheimer's disease therapeutics.

文献摘要

组蛋白去乙酰化酶是一种重要的染色质重塑药物,在阿尔茨海默病的病理生理学与转录失调有关。AD的体外和体内模型显示HDAC活性的过度表达。HDAC的非特异性和非选择性是现有HDAC抑制剂存在的主要问题。因此,我们的目标是建立一个方法学描述合理开发的亚型选择性HDAC抑制剂针对类,I和IIb。一个方便的多级虚拟筛选,然后是机器学习和IC50筛选,将5064个化合物分为抑制剂和非抑制剂两类,从ChEMBL数据库中检索到。ADMET分析确定了所选化合物的药代动力学和药效学特性。分子对接,以及对11种化合物的突变分析,表征了抑制效力。在此,我们首次报道了ChEMBL1834473(2-[[5-(4-氯苯基)-1,3,4-噻二唑-2-基]氨基]-N-羟基嘧啶-5-甲酰胺)作为亚型选择性HDAC抑制剂,与中心Zn2+原子相互作用。ChEMBL1834473与六种HDAC异构体的负能量和相互作用残基也被制成表格和作图。此外,我们的研究发现组氨酸、甘氨酸、苯丙氨酸和天冬氨酸是蛋白质-配体相互作用的关键残基,并将2347种化合物归类为HDAC抑制剂。随后,我们利用PPI网络证明了6个HDAC与参与AD进展和信号通路的关键蛋白的蛋白-蛋白质相互作用网络,该网络描述了ChEMBL1834473与AD之间的关系。综上所述,基于AD治疗学的计算分析,我们得出化合物ChEMBL1834473可能能够抑制I类和IIb类HDAC的所有异构体。


Histone deacetylase enzymes were prominent chromatin remodeling drug that targets in the pathophysiology of Alzheimer's disease associated with transcriptional dysregulation. In vitro and in vivo models of AD have demonstrated overexpression of HDAC activity. Non-specificity and non-selectivity of HDAC are the major problems of existing HDAC inhibitors. Hence, we aim to set up a methodology describing the rational development of isoform-selective HDAC inhibitor targeting class, I and class IIb. A convenient multistage virtual screening followed by machine learning and IC50 screenings were used to classify the 5064 compounds into inhibitors and non-inhibitors classes retrieved from the ChEMBL database. ADMET analysis identified the pharmacokinetics and pharmacodynamics properties of selected compounds. Molecular docking, along with mutational analysis of eleven compounds, characterized the inhibiting potency. Herein, for the first time, we reported ChEMBL1834473 (2-[[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]amino]-N-hydroxypyrimidine-5-carboxamide) as the isoform-selective HDAC inhibitor, which interact central Zn2+ atom. The negative energy and interacting residue of the ChEMBL1834473 with six HDAC isoform has also been tabulated and mapped. Moreover, our findings concluded histidine, glycine, phenylalanine, and aspartic acid as key residues in protein-ligand interaction and classify 2347 compounds as HDAC inhibitors. Later, a protein-protein interaction network of six HDAC with the key proteins involved in the progression of an AD and signaling pathway, which describes the relationship between ChEMBL1834473 and AD, has been demonstrated using PPI network where the chosen inhibitor will work. Altogether, we conclude that the compound ChEMBL1834473 may be capable of inhibiting all isoforms of class I and class IIb HDAC based on computational analysis for AD therapeutics.


获取全文 10.1016/j.lfs.2020.117912