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

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• 作者：John Gately Luz ; Stephen Antonysamy ; Steven L. Kuklish ; Bradley Condon ; Matthew R. Lee ; Dagart Allison ; Xiao-Peng Yu ; Srinivasan Chandrasekhar ; Ryan Backer ; Aiping Zhang ; Marijane Russell ; Shawn S. Chang ; Anita Harvey ; Ashley V. Sloan ; Matthew J. Fisher
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：58
• 期：11
• 页码：4727-4737
• 全文大小：606K
• ISSN：1520-4804

文摘

Microsomal prostaglandin E synthase 1 (mPGES-1) is an 伪-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E₂ (PGE₂) from prostaglandin H₂ (PGH₂). 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 PGH₂ 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鈥揳ctivity 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.