2D, 3D, G-QSAR and Docking Studies of Thiazolyl-pyrazoline Analogues as Potent (Epidermal Growth Factor Receptor-tyrosine Kinase) EGFR-TK Inhibitors

摘要

Background: Cancer is becoming an increasingly important risk factor in the global burden of diseases. Cancer chemotherapy has been one of the major medical advances in the last few decades. However, the drugs used for this therapy have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast, targeted therapy that has been introduced in recent years is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. This paper reviews about 2D, 3D QSAR and G-QSAR on a set of thiazolyl-pyrazole derivatives to identify novel and potent EGFR-TK inhibitors and elucidate structural properties required for anti-EGFR-TK activity. The 2D QSAR studies were carried out by multiple regression method and the r(2) and q(2) values were found to be 0.81 and 0.72 respectively. The 3D QSAR was performed using method k-nearest neighbour-molecular field analysis (kNN-MFA) with simulated annealing variable selection approach; a leave-one-out cross-validated correlation coefficient q2 = 0.87 and non-cross-validated correlation coefficient r2 = 0.93. G-QSAR was performed by generation of multiple models of the same training and test sets as used in 2D & 3D QSAR by multiple linear regressions. G-QSAR was carried out using template based fragmentation scheme and forward variable selection method. Docking analysis was performed further and is suggestive of binding affinity with standard compounds.