Identification of new dasatinib analogues targeting mutated BCR-ABL1: Virtual screening, molecular docking, and dynamics simulations studies

Drug resistance is a significant challenge in cancer chemotherapy and accounts for a large number of cancer-related deaths globally. One of the well-identified and characterized mechanisms of drug resistance is the presence of BCR-ABL1 mutations in chronic myeloid leukaemia (CML). These mutations are associated with resistance to FDA-approved first-line tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, and nilotinib. The present work reports virtual screening, molecular docking, and dynamics simulation results of new-generation anticancer agents. To this end, we performed a three-tier virtual screening to identify three new Dasatinib analogues (45375848, 88575518, and 23589024) selected based on their docking score and ADMET profiles. To understand the affinity, dynamics, and stability of the ligand-protein complexes, a 500 ns MD simulation was carried out and compared. Density functional theory (DFT) at B3LYP was carried out. The three compounds that were identified all contained the common fragment N-(2-chloro-6-methylphenyl)-2-(methylamino)thiazole-5-carboxamide. Docking results predicted that the identified compounds have higher affinity than the dasatinib towards ABL1. The interacting residues were the same as those of the various dasatinib analogues. MD simulations further complemented the docking results, showing stabilization of the ABL1 receptor in the presence of ligands. High drug-likeness and acceptable pharmacokinetic profile warranties the drug-like behaviour of the compounds. This study highlights promising ABL1 inhibitors, laying the groundwork for further in vitro and in vivo investigations.