In Silico Studies of Novel BCL-2 and MCL-1 Inhibitors Using Computational Drug Design Tools

Acute myeloid leukaemia (AML) is an aggressive hematologic malignancy characterized by uncontrolled proliferation of immature myeloid cells, often leading to poor prognosis and high relapse rates. It remains challenging to treat due to resistance driven by anti-apoptotic proteins BCL-2 and MCL-1, which inhibit apoptosis by stabilizing the mitochondrial membrane. Venetoclax, a BCL-2 inhibitor, faces resistance due to MCL-1 upregulation. This study evaluates five novel inhibitors—AZD5991, BRD-810, BFC1108, VU661013, and A-1210477—that target both BCL-2 and MCL-1 to overcome Venetoclax resistance. Computational tools Molinspiration and SwissADME predicted favourable physicochemical and pharmacokinetic properties for these compounds, with BFC1108 showing the best gastrointestinal absorption. ChemDraw was used for chemical structure representation, and Autodock vina 1.5.7 performed molecular docking with 6QBC (MCL-1) and 6FBX (BCL-2). Docking results showed strong binding affinities of all the compounds and exclusively, with AZD5991 binding to MCL-1 similarly to Venetoclax binding to MCL-1. A-1210477 showed superior binding to BCL-2, suggesting potential as a potent complement. Biovia visualized protein-ligand interactions, supporting dual inhibition of BCL-2 and MCL-1 as an effective strategy to induce apoptosis in AML cells resistant to Venetoclax. In conclusion, AZD5991, BRD-810, BFC1108, VU661013, and A-1210477 are promising dual inhibitors for AML treatment. Computational analysis suggests they may overcome Venetoclax resistance with favourable pharmacokinetic profiles.