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Matrix metalloproteinase-13 (MMP-13) has been considered as a promising therapeutic target for osteoarthritis.In this work,the experimental crystal structures of five MMP-13-1igand complexes are used to build the multiple structure-based pharmacophore model of MMP-13 inhibitors.The reliability of pharmacophore model is validated using a decoy set.The pharmacophore model contains four chemical features: two hydrogen bond acceptor (HBA),one hydrophobic (HY) feature,and one riug aromatic (RA) feature.Particularly,the HY feature is found to orient the MMP-13 inhibitors deep into the S1pocket of MMP-13 to produce selective inhibition.By carrying out the screening of pharmacophore model and subsequent molecular docking,the four non-zinc-chelating selective MMP-13 inhibitors of natural products (NP-015973,NP-000814,STOCK1N-24933,and STOCK1N-69443) are identified.It is found that the binding modes of MMP-13 with our screened four natural products are very similar to the reported experimental binding mode of MMP-13 with the most active inhibitor (GG12003,IC50∶ 0.67 nM),and each of them involves the interactions of a ligand with the three amino acid residues Thr226,Lys119,and His201 of MMP-13 receptor.This shows that our modeling results are in good agreement with the relevant experimental results,which strongly supports our screened MMP-13 inhibitors of natural products.These screened natural products may be used as the lead compounds ofMMP-13 inhibitors in the future studies of structural modifications.