title: Discovery of novel, non-acidic mPGES-1 inhibitors by virtual screening with a multistep protocol.
abstract: Microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors are considered as potential therapeutic agents for the treatment of inflammatory pain and certain types of cancer. So far, several series of acidic as well as non-acidic inhibitors of mPGES-1 have been discovered. Acidic inhibitors, however, may have issues, such as loss of potency in human whole blood and in vivo, stressing the importance of the design and identification of novel, non-acidic chemical scaffolds of mPGES-1 inhibitors. Using a multistep virtual screening protocol, the Vitas-M compound library (∼1.3 million entries) was filtered and 16 predicted compounds were experimentally evaluated in a biological assay in vitro. This approach yielded two molecules active in the low micromolar range (IC50 values: 4.5 and 3.8 μM, respectively).
authors.affiliation: Computer Aided Molecular Design (CAMD) Group, Institute of Pharmacy/Pharmaceutical Chemistry, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Noha
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Computer Aided Molecular Design (CAMD) Group, Institute of Pharmacy/Pharmaceutical Chemistry, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria. Electronic address: Daniela.Schuster@uibk.ac.at.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D062105:Molecular Docking Simulation; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: 3D pharmacophore; Inflammation; Kruskal–Wallis test; Virtual screening; mPGES-1