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Molecular Docking and Competitive Binding Study Discovered Different Binding Modes of Microsomal Prostaglandin E Synthase-1 Inhibitors
He, Shan2; Lai, Luhua1,2
2011-12-01
Source PublicationJOURNAL OF CHEMICAL INFORMATION AND MODELING
ISSN1549-9596
Volume51Issue:12Pages:3254-3261
AbstractMicrosomal 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.
DOI10.1021/ci200427k
Indexed BySCI
Language英语
WOS IDWOS:000298315900023
PublisherAMER CHEMICAL SOC
Citation statistics
Cited Times:15[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.iccas.ac.cn/handle/121111/72104
Collection中国科学院化学研究所
Corresponding AuthorLai, Luhua
Affiliation1.Peking Univ, Beijing Natl Lab Mol Sci, State Key Lab Struct Chem Unstable & Stable Speci, Coll Chem & Mol Engn, Beijing 100871, Peoples R China
2.Peking Univ, Ctr Theoret Biol, Beijing 100871, Peoples R China
Recommended Citation
GB/T 7714
He, Shan,Lai, Luhua. Molecular Docking and Competitive Binding Study Discovered Different Binding Modes of Microsomal Prostaglandin E Synthase-1 Inhibitors[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2011,51(12):3254-3261.
APA He, Shan,&Lai, Luhua.(2011).Molecular Docking and Competitive Binding Study Discovered Different Binding Modes of Microsomal Prostaglandin E Synthase-1 Inhibitors.JOURNAL OF CHEMICAL INFORMATION AND MODELING,51(12),3254-3261.
MLA He, Shan,et al."Molecular Docking and Competitive Binding Study Discovered Different Binding Modes of Microsomal Prostaglandin E Synthase-1 Inhibitors".JOURNAL OF CHEMICAL INFORMATION AND MODELING 51.12(2011):3254-3261.
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