Receptor-guided 3D-Quantitative Structure-Activity Relationship and Docking Studies of 6-Substituted 2-Arylaminopurines as CDK2 Kinase Inhibitors

摘要

Cyclin-dependent kinase 2 (CDK2) plays important roles in cell cycle regulation. Owing to its multiple roles in many cancer types, it is considered as a significant target for cancer drug design. In this study, we used docking techniques and 3D-quantitative structure-activity relationship (3D-QSAR) studies on a series of 6-substituted 2-arylaminopurine derivatives as CDK2 kinase inhibitors. Receptor-guided comparative molecular field analysis (CoMFA) (q(2) = 0.653, optimal number of component [ONC] = 6, r(2) = 0.965) and comparative molecular similarity indices analysis (CoMSIA) (q(2) = 0.718, ONC = 6, r(2) = 0.872) models were developed. Validation by progressive scrambling, bootstrapping (BS), and leave-five-out method suggests that the developed 3D-QSAR models (CoMFA and CoMSIA) have reasonable predictive ability and reliability. Docking analysis revealed five hydrogen bond interactions between the compound 13 (most active compound) and CDK2 active site residues namely Glu81, Leu83, and Asp86. Contour map analysis gave comprehensive information regarding favorable and unfavorable substitution groups. Bulky, electropositive, and hydrophobic substitution groups at the R-2 region can enhance the inhibitory activity of compounds whereas electronegative, hydrogen bond donor, and nonhydrophobic substitution groups at the position R-1 will increase the inhibitory activity. Our contour map results can be used as a guideline in designing new potent compounds for CDK2 inhibition.