Virtual Screening and Molecular Dynamics Simulations Identifying Natural Product-Derived Cathepsin K Inhibitors as Potential Therapeutics for Osteoporosis

Osteoporosis is a prevalent skeletal disorder characterized by excessive bone resorption and an increased risk of fragility fracture. Cathepsin K (CatK), a lysosomal cysteine protease predominantly expressed in osteoclasts, is an established target for anti-resorptive drug development. Here, an integrated computational workflow comprising virtual screening, molecular docking, 300 ns molecular dynamics (MD) simulations, molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations, and drug-likeness/ADMET prediction was used to prioritize natural product-derived CatK ligands from the MEGxM database. Among approximately 6500 screened compounds, TOP1 (PubChem ID: 97043052) and TOP2 (PubChem ID: 135765825) showed docking scores of −8.2 and −7.8 kcal/mol, respectively, compared with −6.6 kcal/mol for the comparative reference ligand (STD). Both compounds satisfied Lipinski’s rule of five; however, their predicted ADMET profiles were mixed, including negative predictions for human intestinal absorption for both compounds and compound-specific metabolic and toxicity liabilities. The 300 ns MD trajectories indicated broadly stable CatK ligand complexes. TOP1 showed slightly lower mean RMSD)/RMSF values than TOP2. In contrast, TOP2 exhibited more favorable MM/PBSA binding free energies than TOP1 at both analyzed intervals (−83.45 ± 10.06 and −80.74 ± 10.18 kJ/mol for TOP2 versus −74.28 ± 10.08 and −57.21 ± 15.04 kJ/mol for TOP1), while STD showed the most favorable MM/PBSA binding free energies overall. Collectively, TOP1 and TOP2 exhibited complementary computational profiles and should therefore be regarded as candidates for biochemical and cellular validation rather than confirmed CatK inhibitors or orally suitable drug leads.