LINEAR RESPONSE APPROXIMATION (LRA) APPROACHES FOR CALCULATING BINDING AFFINITIES OF QUINAZOLINE ANALOGUES AS ALK5 INHIBITORS

Quinazoline and its analogues have important therapeutic value in the treatment of cancer to induce apoptosis in cancer cells in a proliferation-independent manner. The binding free energies of quinazoline based inhibitors of kinase were computed using linear interaction energy method with a surface generalized Born (SGB) continuum solvation model in the human ALK5 kinase domain. A training set of 20 quinazoline analogues was used to build a binding affinity model for estimating the free energy of binding for 12 inhibitors (test set) with diverse structural modifications. The root mean square error (RMSE) between the experimental and predicted activity values was 0.02 µM which is comparable to the level of accuracy achieved by the most accurate methods, such as free energy perturbation (FEP) or thermodynamic integration (TI). The correlation coefficient between experimental and predicted activity based on SGB-LIE estimation for the test set compounds is also significant (R² = 0.9693). Low levels of RMSE for the majority of inhibitors establish the structure-based LIE method as an efficient tool for generating more potent and specific inhibitors of kinase by testing rationally designed lead compounds based on quinazoline derivatives.