Molecular docking/dynamic simulations and ADME-TOX-based analysis of phthalimido-1, 3-thiazole derivatives as BCR-ABL inhibitors

Acute lymphoblastic leukemia (ALL) is an aggressive malignancy distinguished by an inferior survival rate, especially Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), which comprises about 20-30% of all ALL cases. It is caused by the BCR-ABL protein, which is produced in cells that contain the Philadelphia (Ph) chromosome and stimulates the bone marrow to produce an excessive number of lymphoblasts. The ABL1 kinase domain has recently garnered significant attention as a promising molecular target for the development of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) treatment. In this research work, a study of the cytotoxic properties of phthalimido-1, 3-thiazole derivatives against the BCR-ABL protein PDB code 4WA9 was carried out using a combination of different computational chemistry methods, including a molecular docking/dynamics study and ADM-T evaluation. Five top hits were identified based on their free energy scores, namely, 4WA9-L18, 4WA9-L19, 4WA9-L20, 4WA9-L21, and 4WA9-L22, which demonstrated better binding affinity (from -7.8 to -8.3 kcal/mol). Furthermore, MD studies support the molecular docking results and validate the stability of the studied complexes under physiological conditions. These results confirm that the hits selected are verifiable inhibitors of the BCR-ABL protein, implying a good correlation between in silico and in vitro studies. Moreover, in silico ADME-TOX studies were used to predict the pharmacokinetic, pharmacodynamic, and toxicological properties of the studied hits. These findings support the future role of phthalimido-1,3-thiazole derivatives against the ALL disease and may help to find a new therapeutic combination of drugs to treat relapsed acute lymphoblastic leukemia and improve overall survival.