Disruption of oncogenic MCL-1-BAX/BAK interaction using integrase inhibitors: insights from a molecular docking and dynamic exploration

Abstract

Abstract Myeloid cell leukemia-1 (MCL-1) is a prominent representative of the BCL-2 antiapoptotic protein family and plays a key role in the dysregulation of programmed cell death. Overexpression of MCL-1 has emerged as a survival and drug resistance mechanism in several malignancies. Currently, there’s no FDA-approved MCL-1 inhibitor in clinical use. Herein, we used drug repurposing to address this unmet therapeutic need. We employed a virtual computing technique to screen a customized library of thirty-one antiviral drugs for potential antagonistic activity against MCL-1. We investigated the dynamic interaction of the hits in the MCL-1 binding pocket using molecular dynamics simulation (MDS). The binding affinity of the hits was validated using MMGBSA, and ADMET properties of the hits were evaluated using the ADMET Lab 2.0 platform. Further, MCL-1 dependent cell lines and drug sensitivity were investigated using the DepMap CRISPRGeneEffect and CTD⌃2 dataset. Our molecular docking and MMGBSA experiment uncovered bictegravir (− 9.7 kcal/mol) and cabotegravir (− 9.3 kcal/mol) as promising inhibitors of MCL-1. Further, these integrase inhibitors exhibited appealing pharmacokinetic profiles. The 100 ns MDS further exemplifies the drugs’ structural stability in the protein active pocket. Also, our DepMap analysis identified an MCL-1 dependent cell line that exhibits moderate sensitivity to four drugs. Our findings suggest that the hit compounds could be repurposed for MCL-1-dependent cancers. However, further studies involving in vitro and in vivo experimental biological models are required to establish their novel anticancer activity. Graphical Abstract

Keywords

• MCL-1
• Bictegravir
• BCL-2
• Cabotegravir
• Inhibitors
• Cancer