title: Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics.
abstract: Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-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-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.
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: John Gately
authors.initials: JG
authors.lastname: Luz
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Antonysamy
authors.affiliation: ‡Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, Indiana 46285, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kuklish
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Bradley
authors.initials: B
authors.lastname: Condon
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Dagart
authors.initials: D
authors.lastname: Allison
authors.affiliation: ‡Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, Indiana 46285, United States.
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Yu
authors.affiliation: ‡Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, Indiana 46285, United States.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Chandrasekhar
authors.affiliation: ‡Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, Indiana 46285, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Backer
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Marijane
authors.initials: M
authors.lastname: Russell
authors.affiliation: †Lilly Biotechnology Center San Diego, 10300 Campus Point Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Chang
authors.affiliation: ‡Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, Indiana 46285, United States.
authors.forename: Anita
authors.initials: A
authors.lastname: Harvey
authors.affiliation: ‡Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, Indiana 46285, United States.
authors.forename: Ashley V
authors.initials: AV
authors.lastname: Sloan
authors.affiliation: ‡Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, Indiana 46285, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D000071876:Prostaglandin-E Synthases; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases