Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics

被引：58

作者：

Luz, John Gately ^{[1
]}

Antonysamy, Stephen ^{[1
]}

Kuklish, Steven L. ^{[2
]}

Condon, Bradley ^{[1
]}

Lee, Matthew R. ^{[1
]}

Allison, Dagart ^{[1
]}

Yu, Xiao-Peng ^{[2
]}

Chandrasekhar, Srinivasan ^{[2
]}

Backer, Ryan ^{[2
]}

Zhang, Aiping ^{[1
]}

Russell, Marijane ^{[1
]}

Chang, Shawn S. ^{[1
]}

Harvey, Anita ^{[2
]}

Sloan, Ashley V. ^{[2
]}

Fisher, Matthew J. ^{[2
]}

机构：

[1] Lilly Biotechnol Ctr San Diego, San Diego, CA 92121 USA

[2] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 11期

关键词：

PROSTAGLANDIN-E SYNTHASE-1; CARDIOVASCULAR EVENTS; MEMBRANE-PROTEINS; INFLAMMATION; RESPONSES; PAIN; MICE; PURIFICATION; ROFECOXIB; DELETION;

D O I：

10.1021/acs.jmedchem.5b00330

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Microsomal prostaglandin E synthase 1 (mPGES-1) is an a-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E-2 (PGE(2)) from prostaglandin H-2 (PGH(2)). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH(2) synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.

引用

页码：4727 / 4737

页数：11

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