Multiple receptor-ligand based pharmacophore modeling and molecular docking to screen the selective inhibitors of matrix metalloproteinase-9 from natural products.
Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors. The reliability of pharmacophore model is validated based on the two different decoy sets and relevant experimental data. The virtual screening, combining pharmacophore model with molecular docking, is performed to identify the selective MMP-9 inhibitors from a database of natural products. The four novel MMP-9 inhibitors of natural products, NP-000686, NP-001752, NP-014331, and NP-015905, are found; one of them, NP-000686, is used to perform the experiment of in vitro bioassay inhibiting MMP-9, and the IC50 value was estimated to be only 13.4 µM, showing the strongly inhibitory activity of NP-000686 against MMP-9, which suggests that our screening results should be reliable. The binding modes of screened inhibitors with MMP-9 active sites were discussed. In addition, the ADMET properties and physicochemical properties of screened four compounds were assessed. The found MMP-9 inhibitors of natural products could serve as the lead compounds for designing the new MMP-9 inhibitors by carrying out structural modifications in the future.
['Gao|Qi|Q|', 'Wang|Yijun|Y|', 'Hou|Jiaying|J|', 'Yao|Qizheng|Q|', 'Zhang|Ji|J|']
D001665:Binding Sites D001688:Biological Products D020134:Catalytic Domain D055808:Drug Discovery D004789:Enzyme Activation D006801:Humans D057927:Hydrophobic and Hydrophilic Interactions D008024:Ligands D020780:Matrix Metalloproteinase 9 D061965:Matrix Metalloproteinase Inhibitors D008958:Models, Molecular D062105:Molecular Docking Simulation D011485:Protein Binding D021281:Quantitative Structure-Activity Relationship D015203:Reproducibility of Results
Pharmacophore model Molecular docking Inhibitor Matrix metalloproteinase-9 Natural product Virtual screening