Discovery of a New Isatin Scaffold for BCR-ABL Tyrosine Kinase Inhibitors Using a Comprehensive Computational Approach

Inserting Isatin (1H indole 2,3-dione) stands out as an exceptionally captivating element in the realm of drug design and development. Hence, there has been a notable focus in numerous anticancer studies on investigating the potential of various derivatives of Isatin (1H indole 2,3-dione), including imines, hydrazones, thiosemicarbazones, and other compounds. Therefore, to develop new compounds with anticipated high activity, a novel series of 40 Isatin derivatives have undergone 3D-QSAR studies as potent anticancer agents against the leukemia cell line (K562). This approach has been pursued due to the significant importance placed on exploring the potential of these derivatives. Through the analysis of graphical contour maps, the generated models yielded favorable statistical outcomes and provided valuable insights into the structural elements that exert a significant influence on the activity. Furthermore, both CoMFA and CoMSIA models have shown suitable reliabilities (q²  =  0.689, 0.772, respectively) and predictive abilities (r²pred  =  0.780, 0.892, respectively). As a result, the design of five new compounds (T1–T5) based on the Isatin moiety, which exhibited remarkable inhibitory activity, has successfully been accomplished. Accordingly, molecular docking and molecular dynamics (MD) simulations of 100 ns have been utilized to examine the interaction mechanism and conformational changes of the newly designed compounds at the binding site of BCR-ABL tyrosine kinase. MD simulation revealed that both compounds T1 and T2 formed stable complexes with BCR-ABL. Additionally, the assessment of the in-silico pharmacokinetic parameters indicates favorable ADMET properties. These findings hold promise for the future development of potent BCR-ABL tyrosine kinase inhibitors.