3D-QSAR Studies on New Benzothiazole-Based Dual Functional Inhibitors of BCR-ABL Kinase Including the T315I Mutant

Background: Chronic Myelogenous Leukemia (CML) is a kind of blood and bone marrow cancer. Tyrosine Kinase Inhibitors (TKIs) play an important role in the treatment of Chronic Myelogenous Leukemia (CML). Objective: The aims of this study are to demonstrate the different binding mode of Benzothiazole- Based analogues with T315I mutant Bcr-Abl and wild-type Bcr-Abl. Methods: In this paper, Self-Organizing Molecular Field Analysis (SOMFA), a simple Three- Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) analysis was performed on these 49 benzothiazole-based derivatives. Results: In this paper, highly predictive SOMFA models ( r2 = 0.748, rcv 2 = 0.720, F value = 124.9, and SEE = 0.761 for T315I mutant Bcr-Abl, r2 = 0.676, rcv 2 = 0.616, F value = 52.98, and SEE = 0.767 for wild-type Bcr-Abl) were obtained, and the generated models were validated using test sets. Conclusion: We obtained the best models of the training set and the statistical results for SOMFA model had a high predictive ability. The contour maps of potent compounds 9b was constructed by SOMFA method and some useful information was obtained for further designing new structures with high activity.