Investigation of the Bcl-2 Inhibition Potential of Drugs Withdrawn from the Clinic Using in silico Methods

Abstract

Apoptosis is essential for tissue homeostasis, and its dysregulation is a hallmark of cancer. The B-cell lymphoma-2 (Bcl-2) protein family, particularly known for its anti-apoptotic role, contributes to tumor survival and chemoresistance. Venetoclax, a selective Bcl-2 inhibitor, has shown notable clinical success; however, resistance and toxicity highlight the need for alternative strategies. This study aimed to explore the inhibitory potential of withdrawn drugs on Bcl-2 using in silico methods to identify candidates for repurposing in anticancer therapy. Withdrawn drugs were retrieved from the DrugBank database and screened via molecular docking using MzDOCK software, with venetoclax as the reference inhibitor. Compounds displaying higher or comparable affinities were analyzed for key interactions, including hydrogen bonds, hydrophobic contacts, and salt bridges within the Bcl-2 binding pocket. Plicamycin showed the strongest binding affinity (-11.5 kJ/mol), surpassing venetoclax (-10.3 kJ/mol). It not only shared common binding residues with the reference molecule but also formed additional stabilizing interactions. Other drugs, such as depreotide, piperacetazine, and phenolphthalein, also demonstrated favorable binding profiles, supporting the feasibility of repurposing withdrawn compounds. Several withdrawn drugs retain valuable scaffolds for targeting Bcl-2. Plicamycin, despite historical toxicity concerns, emerges as a strong candidate for further preclinical evaluation. Modern delivery systems, such as nanoparticle formulations, may improve efficacy while reducing adverse effects. These findings underscore the promise of computational drug repurposing for anticancer discovery and encourage re-examination of withdrawn drugs within contemporary therapeutic contexts.