title: Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents.
abstract: Microsomal prostaglandin E(2) synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC(50) value of 3.2 μM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC(50) = 0.4 μM).
authors.affiliation: Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: De Simone
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.forename: Daniela
authors.initials: D
authors.lastname: Mueller
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058927:5-Lipoxygenase-Activating Proteins / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D014230:Triazoles; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases