In silico design novel (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine derivatives as inhibitors for glycogen synthase kinase 3 based on 3D-QSAR, molecular docking and molecular dynamics simulation

Qingxiu He; Chu Han; Guangping Li; Haiqiong Guo; Yuxuan Wang; Yong Hu; Zhihua Lin; Yuanqiang Wang

doi:10.1016/j.compbiolchem.2020.107328

In silico design novel (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine derivatives as inhibitors for glycogen synthase kinase 3 based on 3D-QSAR, molecular docking and molecular dynamics simulation

Comput Biol Chem. 2020 Oct:88:107328. doi: 10.1016/j.compbiolchem.2020.107328. Epub 2020 Jul 4.

Authors

Qingxiu He¹, Chu Han¹, Guangping Li¹, Haiqiong Guo¹, Yuxuan Wang¹, Yong Hu¹, Zhihua Lin², Yuanqiang Wang³

Affiliations

¹ School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
² School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China; Chongqing the Seventh People's Hospital, Chongqing, 400054, China. Electronic address: zhlin@cqut.edu.cn.
³ School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China; Chongqing the Seventh People's Hospital, Chongqing, 400054, China. Electronic address: wangyqnn@cqut.edu.cn.

PMID: 32688011
DOI: 10.1016/j.compbiolchem.2020.107328

Abstract

Glycogen Synthase Kinase 3 (GSK-3) is a member of cellular kinase with various functions, such as glucose regulation, cellular differentiation, neuronal function and cell apoptosis. It has been proved as an important therapeutic target in type 2 diabetes mellitus and Alzheimer's disease. To better understand their structure-activity relationships and mechanism of action, an integrated computational study, including three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD), was performed on 79 (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine GSK-3 inhibitors. In this paper, we constructed 3D-QSAR using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) method. The results showed that the CoMFA model (q² = 0.743, r² = 0.980) and the CoMSIA model (q² = 0.813, r² = 0.976) had stable and reliable predictive ability. The electrostatic and H-bond donor fields play important roles in the models. The contour maps of the model visually showed the relationship between the activity of compounds and their three-dimensional structure. Molecular docking was used to identify the key amino acid residues at the active site of GSK-3 and explore its binding mode with ligands. Based on 3D-QSAR models, contour maps and the binding feature between GSK-3 and inhibitor, we designed 10 novel compounds with good potential activity and ADME/T profile. Molecular dynamics simulation results validated that Ile62, Val70 and Lys85 located in the active site play a key role for GSK-3 complexed with inhibitors. These results might provide important information for designing GSK-3 inhibitors with high activity.

Keywords: 3D-QSAR; Amine analogues; Glycogen synthase kinase 3; Inhibitor; Molecular docking; Molecular dynamics.

MeSH terms

Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology*
Drug Design*
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Glycogen Synthase Kinase 3 / metabolism
Humans
Molecular Docking Simulation*
Molecular Dynamics Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quantitative Structure-Activity Relationship*

Substances

Amines
Protein Kinase Inhibitors
Glycogen Synthase Kinase 3