title: In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations.
abstract: Checkpoint kinase 1 (Chk1) is an important serine/threonine kinase with a self-protection function. The combination of Chk1 inhibitors and anti-cancer drugs can enhance the selectivity of tumor therapy. In this work, a set of 1,7-diazacarbazole analogs were identified as potent Chk1 inhibitors through a series of computer-aided drug design processes, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and molecular dynamics simulations. The optimal QSAR models showed significant cross-validated correlation q² values (0.531, 0.726), fitted correlation r² coefficients (higher than 0.90), and standard error of prediction (less than 0.250). These results suggested that the developed models possess good predictive ability. Moreover, molecular docking and molecular dynamics simulations were applied to highlight the important interactions between the ligand and the Chk1 receptor protein. This study shows that hydrogen bonding and electrostatic forces are key interactions that confer bioactivity.
authors.affiliation: School of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. m15201835052_2@163.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gao
authors.affiliation: School of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. hanliping108@163.com.
authors.forename: Liping
authors.initials: L
authors.lastname: Han
authors.affiliation: School of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. clab@sit.edu.cn.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Ren
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D015195:Drug Design; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D047428:Protein Kinase Inhibitors; D000071877:Checkpoint Kinase 1
keywords: Chk1 protein; CoMFA; CoMSIA; docking; molecular dynamics