Structure-based Screening for the Non-zinc-chelating Selective MMP-13 Inhibitors of Natural Products

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-ligand 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 ring aromatic (RA) feature. Particularly, the HY feature is found to orient the MMP-13 inhibitors deep into the Si' pocket 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 of MMP-13 inhibitors in the future studies of structural modifications.