title: Docking-based 3D-QSAR study of pyridyl aminothiazole derivatives as checkpoint kinase 1 inhibitors.
abstract: Checkpoint kinase 1 (Chk1) is a promising target for the design of novel anticancer agents. In the present work, molecular docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on pyridyl aminothiazole derivatives as Chk1 inhibitors. AutoDock was used to determine the probable binding conformations of all the compounds inside the active site of Chk1. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed based on the docking conformations and alignments. The CoMFA model produced statistically significant results with a cross-validated correlation coefficient (q2) of 0.608 and a coefficient of determination (r2) of 0.972. The reliable CoMSIA model with q2 of 0.662 and r2 of 0.970 was obtained from the combination of steric, electrostatic and hydrogen bond acceptor fields. The predictive power of the models were assessed using an external test set of 14 compounds and showed reasonable external predictabilities (r(2)pred) of 0.668 and 0.641 for CoMFA and CoMSIA models, respectively. The models were further evaluated by leave-ten-out cross-validation, bootstrapping and progressive scrambling analyses. The study provides valuable information about the key structural elements that are required in the rational design of potential drug candidates of this class of Chk1 inhibitors.
authors.affiliation: a Department of Bio-New Drug Development, College of Medicine , Chosun University , Gwangju 501-759 , Republic of Korea.
authors.forename: A
authors.initials: A
authors.lastname: Balupuri
authors.forename: P K
authors.initials: PK
authors.lastname: Balasubramanian
authors.forename: C G
authors.initials: CG
authors.lastname: Gadhe
authors.forename: S J
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D000071877:Checkpoint Kinase 1; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases; D021281:Quantitative Structure-Activity Relationship; D013844:Thiazoles / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1
keywords: 3D-QSAR; Chk1; CoMFA; CoMSIA; docking; pyridyl aminothiazoles