Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 10, Pages 2505-2517Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.03.047
Keywords
ROCK inhibitors; ROCK/PKA selectivity; 3D-QSAR; Molecular docking; Molecular dynamics simulations
Funding
- Science and Technology Commission of Shanghai Municipality [12ZR1431100]
- National Natural Science Foundation of China [21172148]
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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. (C) 2015 Elsevier Ltd. All rights reserved.
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