Discovery of bis-aryl urea derivatives as potent and selective Limk inhibitors: Exploring Limk1 activity and Limk1/ROCK2 selectivity through a combined computational study

Jiaxin Cui; Mei Ding; Wei Deng; Yan Yin; Zhonghua Wang; Hong Zhou; Guofeng Sun; Yu Jiang; Yangbo Feng

doi:10.1016/j.bmc.2015.10.041

Discovery of bis-aryl urea derivatives as potent and selective Limk inhibitors: Exploring Limk1 activity and Limk1/ROCK2 selectivity through a combined computational study

Bioorg Med Chem. 2015 Dec 1;23(23):7464-77. doi: 10.1016/j.bmc.2015.10.041. Epub 2015 Oct 30.

Authors

Jiaxin Cui¹, Mei Ding¹, Wei Deng¹, Yan Yin², Zhonghua Wang¹, 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.

PMID: 26545798
DOI: 10.1016/j.bmc.2015.10.041

Abstract

Lim kinase (Limk), a proline/serine-rich sequence, can regulate the polymerization of the actin filaments by phosphorylating, and it is found to be highly involved in various human diseases. In this paper, 47 reported Limk1 inhibitors with bis-aryl urea scaffold were used to design potent and selective Limk inhibitors by computational approaches. Firstly, the structure-Limk1 activity relationship models (3D-QSAR) and structure-Limk1/ROCK2 selectivity relationship models (3D-QSSR) were developed and both 3D-QSAR and 3D-QSSR models showed good correlative and predictive abilities. Then, the molecular docking and molecular dynamics (MD) simulations were employed to validate the optimal docking conformation and explore the binding affinities. Finally, five new compounds were designed and all of them exhibited good Limk1 inhibition and Limk1/ROCK2 selectivity after synthesis and biological evaluation, which demonstrated that the obtained information from computational studies were valuable to guide Limk inhibitors' design.

Keywords: Limk1 inhibitors; Limk1/ROCK2 selectivity; Molecular docking; Molecular modeling; Urea derivatives.

Publication types

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

MeSH terms

Humans
Lim Kinases / antagonists & inhibitors*
Lim Kinases / chemistry
Molecular Docking Simulation
Molecular Dynamics Simulation
Phenylurea Compounds / chemical synthesis
Phenylurea Compounds / chemistry*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Quantitative Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / chemistry

Substances

Phenylurea Compounds
Protein Kinase Inhibitors
LIMK1 protein, human
Lim Kinases
ROCK2 protein, human
rho-Associated Kinases