Harnessing bioactive phytoconstituents to inhibit cathepsin K: a promising approach for therapeutic development against osteoporosis

Osteoporosis is a chronic disease characterized by low mass bone and high susceptibility to fracture due to the disrupted equilibrium between osteoclast-mediated bone resorption and osteoblast-driven bone formation. Cathepsin K (CatK) is a cysteine protease predominantly expressed in osteoclasts and is essential for bone matrix degradation during resorption, thus making it a promising therapeutic target. In this study, we used an integrated bioinformatics approach to explore the possible use of bioactive phytoconstituents as CatK inhibitors. Virtual screening of phytoconstituents from the IMPPAT-2 database was performed as guided by physicochemical predictions and Pan-assay interference compounds (PAINS) filters. Docking analysis, pharmacokinetic profiling, and PASS predictions identified Digalogenin and Withametelin F as promising candidates with appreciable affinity and favorable interactions with CatK’s active site. Molecular dynamics (MD) simulations confirmed the conformational stability of Digalogenin and Withametelin F with the CatK binding site. Free energy calculations further supported their inhibitory potential towards CatK. Our results suggest that Digalogenin and Withametelin F may represent promising lead compounds for developing plant-derived therapeutics for osteoporosis. However, these findings require experimental validation to confirm binding efficacy, selectivity, and to exclude off-target effects.