Disruption of Oncogenic MCL-1-BAX/BAK Interaction Using Integrase Inhibitors: Insights from a Molecular Docking and Dynamic Exploration

Abstract Dysregulation of programmed cell death is a hallmark characteristic of cancer cells, making the apoptotic signaling pathway of important clinical relevance in cancer therapy. In mammalian cells, this critical cellular event is negatively regulated by antiapoptotic BCL-2 proteins. Notably, overexpression of Myeloid Cell Leukemia-1 (MCL-1) has emerged as a survival and drug resistance mechanism in several malignancies. Given its high oncogenic potential, MCL-1 represents an attractive therapeutic target for solid and hematological tumors. Oncological drug development is prohibitively expensive, time-consuming, and has a poor success rate due to toxic side effects. Thus, repurposing existing approved drugs with demonstrated safety profiles denotes a promising strategy for rapidly and economically discovering drugs in cancer medicine. Herein, we used a virtual computing technique to screen a customized library of thirty-one antiviral drugs for potential antagonistic activity against MCL-1. Our molecular docking experiment uncovered bictegravir and cabotegravir as promising inhibitors of MCL-1 in comparison to the reference clinical inhibitor (AMG176) based on superior binding affinity and strong interactions with the protein hotspots residues. Further, these integrase inhibitors exhibited appealing pharmacokinetic and toxicity profiles. Noteworthy, the thermodynamic parameters studied during the 100 ns molecular dynamics (MD) simulation and principal component analysis of the MD trajectory exemplify these drugs' structural stability and conformational flexibility in the protein active pocket. Our findings suggest that these integrase inhibitors could be repurposed for cancers overexpressing MCL-1. However, further studies involving experimental biological models are required to unravel their novel anticancer activity and ascertain their clinical efficacy in cancer treatment.