Macitentan as a repurposed MCL-1 inhibitor in triple-negative breast cancer: Insights from molecular docking, MM-GBSA, and MD simulations

Abstract

Triple-negative breast cancer (TNBC) remains a significant clinical challenge due to its aggressive nature and lack of targeted therapies. Overexpression of myeloid cell leukemia-1 (MCL-1) and polo-like kinase 1 (PLK1) contributes to tumor progression and therapeutic resistance, making them making them attractive therapeutic targets. This study explores the repurposing potential of FDA-approved endothelin receptor antagonists (ERAs); Macitentan, Ambrisentan, and Bosentan against MCL-1 and PLK1 using a comprehensive computational approach. Molecular docking, molecular mechanics-generalized born surface area (MM-GBSA) binding free energy calculations and molecular dynamics (MD) simulations analyses were employed to evaluate binding affinity and complex stability. Macitentan demonstrated the strongest binding to both targets, particularly MCL-1, with favorable docking (–9.023 kcal/mol) and MM-GBSA (–48.53 kcal/mol) scores, while Ambrisentan showed moderate affinity. Benchmarking with co-crystallized ligands confirmed the superior binding of R78 to PLK1, shifting the study’s focus to MCL-1. MD simulations confirmed the stability of Macitentan and Ambrisentan complexes with MCL-1, maintaining the root mean square deviation (RMSD) < 3.5 Å with minor drift around 4 Å and root mean square fluctuation (RMSF) < 2.5 Å. These findings support further experimental validation of Macitentan as a repurposed MCL-1 targeted therapy for TNBC.