Targeting myeloid cell leukemia-1 protein to identify potential compounds for chronic myeloid leukemia treatment: Molecular docking and molecular dynamics simulation approaches.

Myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic member of the Bcl-2 family, is frequently overexpressed and amplified in chronic myeloid leukemia (CML) as well as in several other malignancies, contributing to tumor progression and therapeutic resistance. The present study employed a multi-step virtual screening approach to identify potential inhibitors of the Mcl-1 protein and subsequently validated their inhibitory activity through computational approaches. The 3-D structure of Mcl-1 protein was retrieved from the protein data bank and subjected to structure-based virtual screening. A series of drug-likeness and ADMET filters, including Lipinski filter, Swiss ADME, ADME-Tox, pKCSM and Protox-3 web, were applied to prioritize the compounds with favorable pharmacokinetic and toxicity profile. Further evaluated by molecular docking, with particular emphasis on -CDOCKER interaction energy, identified tolbutamide (-101.09 kcal/mol), leucodelphinidin (-89.304 kcal/mol), and gossypetin -70.49 (kcal/mol) as, most promising candidates. To assess the conformational stability and dynamic behavior of the protein-ligand complexes, molecular dynamics simulation was performed for 100ns and extended to 500 ns for the best screened compound. Trajectory analysis was conducted using multiple descriptors, including root mean square deviation, root mean square fluctuation, the radius of gyration, solvent-accessible surface area (SASA), hydrogen bonds, and free energy landscape. In vitro toxicity studies using the MTT assay on the K562 chronic myeloid leukemia cell line demonstrated a significant reduction in cell viability, indicating potent antiproliferative activity. These computational studies highlight novel compounds as potent Mcl-1 inhibitors, suggesting their potential as promising therapeutic candidates for the treatment of CML. These findings lay the foundation for further optimization and preclinical evaluation of Mcl-1 targeted compounds in cancer therapy.