Design and Computational Evaluation (Docking) of quinazoline–piperazine carboxamide derivatives as Potential Tyrosine Kinase Inhibitors.

Abstract

The abnormal regulation of c-ABL tyrosine kinase linked with the BCR-ABL fusion gene remains the primary therapeutic focus in the management of Chronic Myeloid Leukemia (CML). While inhibitors such as Imatinib have shown notable clinical efficacy, the development of resistance mutations creates the need for new therapeutic candidates. In this regard, the present study reports the rational design and computational screening of a novel set of compounds, namely quinazoline–piperazine carboxamide derivatives, as prospective ATP-competitive inhibitors. These hybrid molecules were designed by merging the kinase inhibitory characteristics of the quinazoline core with the structural properties of the piperazine-carboxamide moiety. Molecular docking studies against the c-ABL kinase domain (PDB ID: 1IEP) identified high-affinity lead compounds with strong structural compatibility in the ATP-binding pocket. Interaction analysis demonstrated stable hydrogen bond formation in the hinge region along with notable stabilization of the DFG motif, indicating the anticancer potential of these derivatives. These outcomes offer a strong theoretical basis for further chemical synthesis and biological evaluation.