title: Pharmacophore modeling and virtual screening for novel acidic inhibitors of microsomal prostaglandin E₂ synthase-1 (mPGES-1).
abstract: Microsomal prostaglandin E(2) synthase-1 (mPGES-1) catalyzes prostaglandin E(2) formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC(50) values between 0.4 and 7.9 μM, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC(50) values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGES-1 are presented that may possess anti-inflammatory properties based on the interference with eicosanoid biosynthesis.
authors.affiliation: Institute of Pharmacy, Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Waltenberger
authors.forename: Katja
authors.initials: K
authors.lastname: Wiechmann
authors.forename: Julia
authors.initials: J
authors.lastname: Bauer
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Noha
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D016208:Databases, Factual; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology*; D008958:Models, Molecular; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D002264:Carboxylic Acids; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases