title: 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.
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.
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
authors.forename: Ding
authors.initials: D
authors.lastname: Mei
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
authors.forename: Fanhong
authors.initials: F
authors.lastname: Wu
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Cui
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Sun
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Florida, Jupiter, FL 33458, USA. Electronic address: yfeng@scripps.edu.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
mesh_terms: D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D055808:Drug Discovery; D057075:Enzyme Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*; D055672:Static Electricity; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014508:Urea; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: 3D-QSAR; Molecular docking; Molecular dynamics simulations; ROCK inhibitors; ROCK/PKA selectivity