Molecular Docking/Dynamic Simulations and ADME-TOX-Based Analysis of Phthalimido-1,3-Thiazole Derivatives as BCR-ABL Inhibitors

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood. 30–50% of its cases are caused by the BCR-ABL1 fusion gene as a driver oncogene. In this research work, a study of the cytotoxic properties of phthalimido-1,3- thiazole derivatives against the BCR-ABL protein PDB ID: 4WA9 was carried out using a combination of different computational chemistry methods, including a molecular docking/dynamics study and ADM-T evaluation. Six top hits were identified based on their free energy scores E score (Kcaol/mol), namely 4WA9-L21, 4WA9-L20, 4WA9-L22, 4WA9-L19, 4WA9-L18 , and 4WA9-L18, which demonstrated better binding affinity (from -8.36 to −9.29 kcal/mol). Furthermore, Molecular dynamics simulation 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, pharmacodynamics, and toxicological properties of the studied hits. These findings support the future role of phthalimido-1,3-thiazole derivatives against the Acute lymphoblastic leukemia disease and may help to find a new therapeutic combination of drugs to treat relapsed acute lymphoblastic leukemia and improve overall survival.