Repurposing halofuginone derivatives for osteoarthritis therapy: Structural insights, multi-target inhibition, and pharmacokinetic profiling

Osteoarthritis is a degenerative joint disease characterized by progressive cartilage degradation, leading to pain and reduced mobility. This study employed a computational approach to explore the therapeutic potential of halofuginone and MAZ1310 as novel inhibitors targeting osteoarthritis-related pathways. Molecular docking was performed to evaluate the binding affinities of these compounds with key proteins involved in osteoarthritis pathogenesis, including MMP3, MMP13, SERPINA1, and BMP1. Molecular dynamics (MD) simulations were conducted to assess the stability of the ligand-protein complexes, followed by MM-PBSA calculations to estimate their binding free energies. Pharmacokinetic analyses were performed to determine absorption, distribution, metabolism, and excretion (ADME) properties, while toxicity profiling evaluated potential safety risks. The results revealed that halofuginone exhibited strong and stable binding interactions with multiple osteoarthritis-related proteins, particularly MMP3 and MMP13, suggesting its role in preventing cartilage breakdown. MAZ1310 also showed promising activity but displayed solubility limitations, necessitating formulation optimization. Toxicity assessments identified febrifugine as a potential risk due to its cardiotoxic effects. These findings highlight the potential of halofuginone and MAZ1310 as osteoarthritis therapeutics and emphasize the need for further preclinical and clinical validation to confirm their efficacy and safety profiles.