Structure-based Screening for the Non-zinc-chelating Selective MMP-13 Inhibitors of Natural Products
邹庆;高秋爽;姚芃;姚其正;张骥
a (Department of Physical Chemistry, China Pharmaceutical University, Nanjing 210009, China)
b (State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China)
c (School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China)
Structure-based Screening for the Non-zinc-chelating Selective MMP-13 Inhibitors of Natural Products
ZOU Qing;GAO Qiu-Shuang;YAO Peng;YAO Qi-Zheng;ZHANG Ji
a (Department of Physical Chemistry, China Pharmaceutical University, Nanjing 210009, China)
b (State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China)
c (School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China)
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 S1' 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.
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 S1' 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.
邹庆;高秋爽;姚芃;姚其正;张骥. Structure-based Screening for the Non-zinc-chelating Selective MMP-13 Inhibitors of Natural Products[J]. 结构化学, 2020, 39(11): 1990-2000.
ZOU Qing;GAO Qiu-Shuang;YAO Peng;YAO Qi-Zheng;ZHANG Ji. Structure-based Screening for the Non-zinc-chelating Selective MMP-13 Inhibitors of Natural Products. CHINESE JOURNAL OF STRUCTURAL CHEMISTRY, 2020, 39(11): 1990-2000.
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2020, Vol. 39 
