当前位置： SCI文献检索 > JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS期刊下所有文献 > In silico studies on p21-activated kinase 4 inhibitors: comprehensive application of 3D-QSAR analysis, molecular docking, molecular dynamics simulations, and MM-GBSA calculation.

In silico studies on p21-activated kinase 4 inhibitors: comprehensive application of 3D-QSAR analysis, molecular docking, molecular dynamics simulations, and MM-GBSA calculation.

Abstract：

:P21-activated kinase 4 (PAK4) is a serine/threonine protein kinase, which is associated with many cancer diseases, and thus being considered as a potential drug target. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations were performed to explore the structure-activity relationship of a series of pyrropyrazole PAK4 inhibitors. The statistical parameters of comparative molecular field analysis (CoMFA, Q2 = 0.837, R2 = 0.990, and R2pred = 0.967) and comparative molecular similarity indices analysis (CoMSIA, Q2 = 0.720, R2 = 0.972, and R2pred = 0.946) were obtained from 3D-QSAR model, which exhibited good predictive ability and significant statistical reliability. The binding mode of PAK4 with its inhibitors was obtained through molecular docking study, which indicated that the residues of GLU396, LEU398, LYS350, and ASP458 were important for activity. Molecular mechanics generalized born surface area (MM-GBSA) method was performed to calculate the binding free energy, which indicated that the coulomb, lipophilic and van der Waals (vdW) interactions made major contributions to the binding affinity. Furthermore, through 100 ns MD simulations, we obtained the key amino acid residues and the types of interactions they participated in. Based on the constructed 3D-QSAR model, some novel pyrropyrazole derivatives targeting PAK4 were designed with improved predicted activities. Pharmacokinetic and toxicity predictions of the designed PAK4 inhibitors were obtained by the pkCSM, indicating these compounds had better absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. Above research provided a valuable insight for developing novel and effective pyrropyrazole compounds targeting PAK4.

journal_name

J Biomol Struct Dyn

journal_title

Journal of biomolecular structure & dynamics

authors

Gao Y,Wang H,Wang J,Cheng M

doi

10.1080/07391102.2019.1673823

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

4119-4133

issue

eissn

0739-1102

issn

1538-0254

journal_volume

pub_type

杂志文章

在线工具

In silico studies on p21-activated kinase 4 inhibitors: comprehensive application of 3D-QSAR analysis, molecular docking, molecular dynamics simulations, and MM-GBSA calculation.