Investigating the binding mechanism of piperidinyl ureas inhibitors based on the UBC12-DCN1 interaction by 3D-QSAR, molecular docking and molecular dynamics simulations

分子动力学 化学 数量结构-活动关系 接合作用 对接(动物) 分子模型 立体化学 蛋白质-蛋白质相互作用 NEDD8公司 计算生物学 计算化学 泛素 生物化学 生物 泛素连接酶 护理部 基因 医学
作者
Jiangheng Zhao,Jieying Zang,Jing Yang,Qi-Bing Gao,Ying Yan,Chao-Ya Ma,Yujie Chen,Lina Ding,Hong‐Min Liu
出处
期刊:Journal of Biomolecular Structure & Dynamics [Taylor & Francis]
卷期号:40 (6): 2674-2688 被引量:2
标识
DOI:10.1080/07391102.2020.1841678
摘要

Neddylation regulates a variety of biological processes by modulating Cullin-RING E3 ubiquitin ligases (CRLs) which is considered to be an important target for human diseases. The activation of CRLs required Cullins Neddylation, which regulated by the interaction of UBC12-DCN1 complex. Here, to investigate the structure-activity relationship and binding mechanism of 41 piperidinyl ureas inhibitors based on the UBC12-DCN1 protein-protein interaction, we carried out molecular modeling studies using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations.Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q2=0.736, r2ncv=0.978, r2pred=0.78 (CoMFA), and the best CoMSIA model has q2=0.761, r2ncv=0.987, r2pred=0.86. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300 K. The results of MM-GBSA indicated the residues of Ile1083, Ile1086, Ala1098, Val1102, Ile1105, Gln1114, Phe1164 and Leu1184 might be the key residues during the process of inhibitors bound to DCN1. This study could provide an important theoretical basis for further developing novel inhibitors design based on UBC12-DCN1 protein-protein interaction. All the results can provide us more useful information for our further drug design. Communicated by Ramaswamy H. Sarma.
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