Molecular modeling studies of Rho kinase inhibitors using molecular docking and 3D-QSAR analysis

• Published in: European journal of medicinal chemistry 2010-07, Vol.45 (7), p.2768-2776
• Main Authors: Qin, Jin, Lei, Beilei, Xi, Lili, Liu, Huanxiang, Yao, Xiaojun
• Format: Article
• Language: English
• Subjects: 3D-QSAR; Biological and medical sciences; CoMFA; CoMSIA; Docking; General pharmacology; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Quantitative Structure-Activity Relationship; Rho kinase; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - chemistry; rho-Associated Kinases - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.02.059

Rho kinase (ROCK) has become an attractive target for the treatment of many diseases such as hypertension, stroke and cancer. In this work, molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were performed on a series of ROCK inhibitors. Molecular docking was used to explore the binding mode between the ligands and the receptor. Based on the docked conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to gain insights into the key structural factors affecting the activity. The results of the molecular modeling studies suggested that further modification of these inhibitors with bulky and hydrophobic groups that accommodated in the distal region of the ROCK binding pocket would improve the activity. [Display omitted]