title: Discovery of bis-aryl urea derivatives as potent and selective Limk inhibitors: Exploring Limk1 activity and Limk1/ROCK2 selectivity through a combined computational study.
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.
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd, Shanghai 201418, PR China.
authors.forename: Jiaxin
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: Mei
authors.initials: M
authors.lastname: Ding
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd, Shanghai 201418, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
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: Zhonghua
authors.initials: Z
authors.lastname: Wang
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.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
mesh_terms: D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases
keywords: Limk1 inhibitors; Limk1/ROCK2 selectivity; Molecular docking; Molecular modeling; Urea derivatives