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

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.

Author information

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.

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

PMID:
25882521
DOI:
10.1016/j.bmc.2015.03.047
[Indexed for MEDLINE]

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