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Purpose: To identify natural chemiome that inhibits matrix-metalloproteinases (MMPs) with a view to discovering novel disease-modifying osteoarthritis drugs (DMOADs). Methods: Computer-aided drug design (CADD) with virtual screening, ADME/Tox, molecular docking, molecular dynamics simulation, and MM-PBSA calculations were used in search of novel natural compounds that inhibit MMPs. Results: From more than fifty thousand compounds, a single lead compound (IBS ID: 77312) was shortlisted using bias based on binding energy and drug-likeness. This lead compound synergistically bound to the S1 domain of MMP-13 protein through five hydrogen bonds. The interactions became stable within 100-nanosecond molecular dynamics simulation run. The in vitro data for the lead compound showed that its minimal non-lethal dose increased collagen content but decreased aggrecan level in chondrocytes. Conclusion: This study has identified a natural lead compound that may pave the way for a novel DMOAD of natural origin against OA. Keywords: Osteoarthritis, MMP-13, Natural chemiome, Disease-modifying osteoarthritis drug, Molecular docking

Structural analysis and insight into novel MMP-13 inhibitors from natural chemiome as disease-modifying osteoarthritis drugs