Name
Title | ||
|---|---|---|
Molecular docking and competitive binding study discovered different binding modes of microsomal prostaglandin E synthase-1 inhibitors. |
Abstract | ||
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Microsomal prostaglandin E synthase-1 (mPGES-1) is a newly recognized therapeutic target for the treatment of inflammation, pain, cancer, atherosclerosis, and stroke. Many mPGES-1 inhibitors have been discovered. However, as the structure of the binding site is not well-characterized, none of these inhibitors was designed based on the mPGES-1 structure, and their inhibition mechanism remains to be fully disclosed. Recently, we built a new structural model of mPGES-1 which was well supported by experimental data. Based on this model, molecular docking and competition experiments were used to investigate the binding modes of four representive mPGES-1 inhibitors. As the inhibitor binding sites predicted by docking overlapped with both the substrate and the cofactor binding sites, mPGES-1 inhibitors might act as dual-site inhibitors. This inhibitory mechanism was further verified by inhibitor-cofactor and inhibitor-substrate competition experiments. To investigate the potency-binding site relationships of mPGES-1 inhibitors, we also carried out molecular docking studies for another series of compounds. The docking results correlated well with the different inhibitory effects observed experimentally. Our data revealed that mPGES-1 inhibitors could bind to the substrate and the cofactor binding sites simultaneously, and this dual-site binding mode improved their potency. Future rational design and optimization of mPGES-1 inhibitors can be carried out based on this binding mechanism. |
Year | DOI | Venue |
|---|---|---|
2011 | 10.1021/ci200427k | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
Field | DocType | Volume |
Microsome,Docking (molecular),Cofactor,Binding site,Microsomal Prostaglandin E Synthase-1,Docking (dog),Biochemistry,Chemistry,Prostaglandin E,Stereochemistry,Inflammation | Journal | 51 |
Issue | ISSN | Citations |
12 | 1549-9596 | 0 |
PageRank | References | Authors |
0.34 | 3 | 2 |