Rational design and computational screening of febrifugine analogues as selective MMP inhibitors for osteoarthritis treatment

Osteoarthritis (OA) is a degenerative joint disorder that primarily affects aging populations, resulting in progressive cartilage degradation and joint dysfunction. The pathological role of matrix metalloproteinases (MMPs), particularly MMP-1, MMP-8, and MMP-13, in extracellular matrix breakdown highlights them as attractive therapeutic targets. This study investigated the inhibitory potential of febrifugine analogs against these collagenases using molecular docking and molecular dynamics (MD) simulations. Computational methods were employed to evaluate binding affinities, stability, and pharmacokinetic profiles of the compounds. Among the tested compounds, Compound 19 exhibited the most favorable binding energies, with -118.788 kJ/mol for MMP-8, -96.532 kJ/mol for MMP-13, and -72.528 kJ/mol for MMP-1. Molecular dynamics simulations validated the stability of Compound 19 complexes over a 200 ns trajectory, as indicated by stable root mean square deviation (RMSD) and radius of gyration (Rg) values. The MM/PBSA free energy decomposition analysis revealed significant contributions from van der Waals and electrostatic interactions, further confirming the binding efficiency. Pharmacokinetic assessments showed that Compound 19 adhered to Lipinski’s rule of five, with favorable absorption, distribution, metabolism, and excretion (ADME) characteristics. These results highlight Compound 19 as a potent inhibitor with strong selectivity for MMP-8, making it a promising candidate for osteoarthritis therapy. Further experimental validation is required to confirm its efficacy and explore structure-activity relationships for improved selectivity and safety. This study underscores the potential of febrifugine-based analogs in advancing disease-modifying treatments for osteoarthritis.