Discovery of potent and selective urea-based ROCK inhibitors: Exploring the inhibitor's potency and ROCK2/PKA selectivity by 3D-QSAR, molecular docking and molecular dynamics simulations

Ding Mei; Yan Yin; Fanhong Wu; Jiaxing Cui; Hong Zhou; Guofeng Sun; Yu Jiang; Yangbo Feng

doi:10.1016/j.bmc.2015.03.047

Discovery of potent and selective urea-based ROCK inhibitors: Exploring the inhibitor's potency and ROCK2/PKA selectivity by 3D-QSAR, molecular docking and molecular dynamics simulations

Bioorg Med Chem. 2015 May 15;23(10):2505-17. doi: 10.1016/j.bmc.2015.03.047. Epub 2015 Mar 25.

Authors

Ding Mei¹, Yan Yin², Fanhong Wu¹, Jiaxing Cui¹, Hong Zhou¹, Guofeng Sun¹, Yu Jiang¹, Yangbo Feng³

Affiliations

¹ School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
² School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China; Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Rd., Shanghai 200032, PR China. Electronic address: yinyan@sit.edu.cn.
³ Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Florida, Jupiter, FL 33458, USA. Electronic address: yfeng@scripps.edu.

PMID: 25882521
DOI: 10.1016/j.bmc.2015.03.047

Abstract

An activity model and a selectivity model from 3D-QSAR studies were established by CoMFA and CoMSIA to explore the SAR. Then docking was used to study the binding modes between ligand and kinases (ROCK2 and PKA), and the molecular docking results were further validated by MD simulations. Computational results suggested that substitution containing positive charge attached to the middle phenyl ring, or electropositive group in urea linker was favored for both activity and ROCK2/PKA selectivity. Finally, three compounds were designed, and biological evaluation demonstrated that these molecular models were effective for guiding the design of potent and selective ROCK inhibitors.

Keywords: 3D-QSAR; Molecular docking; Molecular dynamics simulations; ROCK inhibitors; ROCK/PKA selectivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
Cyclic AMP-Dependent Protein Kinases / chemistry
Drug Discovery
Enzyme Assays
Humans
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Quantitative Structure-Activity Relationship
Recombinant Proteins / chemistry*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry*
Static Electricity
Urea / analogs & derivatives
Urea / chemical synthesis
Urea / chemistry*
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / chemistry

Substances

Ligands
Protein Kinase Inhibitors
Recombinant Proteins
Small Molecule Libraries
Urea
ROCK2 protein, human
rho-Associated Kinases
Cyclic AMP-Dependent Protein Kinases