Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis and molecular docking of ATP-competitive triazine analogs of human mTOR inhibitors

Abstract

The mTOR (mammalian target of rapamycin), a serine/threonine kinase has been identified as an important target for cancer. A 3D-QSAR analysis was carried out on 40 triazine based analogs of ATP-competitive mTOR kinase inhibitors. The study includes molecular field analysis (MFA) with G/PLS to predict the steric and electrostatic molecular field requirement for the activity of inhibitors. The QSAR model was developed using a training set of 33 compounds. The analyzed MFA model revealed a good fit, having r 2 value of 0.897 and r cv2 value of 0.718. The predictive power of the model generated was validated using a test set comprising 7 molecules with r pred2 value of 0.826. The analysis of the best MFA model provided insights into the structure-activity correlation of mTOR kinase inhibitors. Molecular docking studies revealed that all inhibitors bind in the ATP pocket of the kinase domain. Our QSAR model and molecular docking results corroborate with each other and propose directions for the design of new inhibitors with better activity toward mTOR kinase. © Springer Science+Business Media, LLC 2011.