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

• 作者: GAO Qiu-Shuang YAO Peng YAO Qi-Zheng ZHANG Ji ZOU Qing
• 来源期刊: 结构化学
• 年，卷（期）: 2020,（11）
• 所属期刊栏目: medicinal structural chemistry
• 页码范围: 1990-2000
• 页数: 11页
• 语种: 英文
• DOI: 10.14102/j.cnki.0254-5861.2011-2831

摘要

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 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 ofMMP-13 inhibitors in the future studies of structural modifications.