Citation: Qing ZOU, Qiu-Shuang GAO, Peng YAO, Qi-Zheng YAO, Ji ZHANG. Structure-based Screening for the Non-zinc-chelating Selective MMP-13 Inhibitors of Natural Products[J]. Chinese Journal of Structural Chemistry, ;2020, 39(11): 1990-2000. doi: 10.14102/j.cnki.0254–5861.2011–2831 shu

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

Qing ZOU ^a ,
Qiu-Shuang GAO ^a ,
Peng YAO ^a ,
Qi-Zheng YAO ^c ,
Ji ZHANG ^{a, b,,}

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

Corresponding author: Ji ZHANG,
Received Date: 31 March 2020
Accepted Date: 8 July 2020

Figures(8)

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,
- non-zinc-chelating inhibitor of MMP-13,
- pharmacophore model,
- molecular docking,
- screening
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