Repurposing bicalutamide as a potential inhibitor of MMP13 for osteoarthritis treatment

Osteoarthritis (OA) is a prevalent degenerative joint disease affecting millions worldwide, characterized by cartilage degradation and joint inflammation. Current treatments primarily alleviate symptoms but fail to halt disease progression, underscoring the need for disease-modifying therapies. This study explored the repurposing of bicalutamide, a selective androgen receptor antagonist used in prostate cancer, as a potential MMP-13 inhibitor to target cartilage degradation in OA. Using molecular docking, 250-nanosecond molecular dynamics simulations, MM-PBSA binding energy calculations, and ADMET profiling, we compared bicalutamide against diacerein and BI-4394 using validated MMP-13 structure (PDB: 5BPA). Bicalutamide demonstrated moderate binding affinity (docking score: -5.06) with favourable MM-PBSA energy (-45.148 ± 1.512 kJ/mol). Remarkably, molecular dynamics revealed bicalutamide induced the greatest MMP-13 structural stabilization, exhibiting lowest protein RMSD (0.384 ± 0.046 nm) and RMSF values (0.137 ± 0.112 nm). ADMET analysis showed bicalutamide’s advantage as non-CYP450 3A4 substrate, reducing drug-drug interaction risks. This first computational study elucidated a unique, structure-stabilizing mechanism by which bicalutamide inhibited MMP-13, representing a notable departure from conventional competitive inhibitors. Collectively, these findings supported bicalutamide’s potential as a disease-modifying therapeutic for osteoarthritis and strongly warranted further experimental validation to advance its clinical application.