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

• Ngôn ngữ: eng
• Ký hiệu phân loại: 572.4 *Metabolism
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: p. 4727-4737 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261179
• Chủ đề: 1. 60 applied life sciences; 2. Crystal structure; 3. Imidazoles; 4. Inhibitors; 5. Monomers; 6. Rodent models

Tóm tắt

 Microsomal prostaglandin E synthase 1 (mPGES-1) is an ?-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E<
 sub>
 2<
 /sub>
  (PGE<
 sub>
 2<
 /sub>
 ) from prostaglandin H<
 sub>
 2<
 /sub>
  (PGH<
 sub>
 2<
 /sub>
 ). 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<
 sub>
 2<
 /sub>
  synthesis and avoiding suppression of antithrombotic prostacyclin production. In this work, 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.