title: A facilitated approach to evaluate the inhibitor mode and potency of compounds targeting microsomal prostaglandin e synthase-1.
abstract: Microsomal prostaglandin E(2) synthase-1 (MPGES1) catalyzes the formation of prostaglandin E(2) from the endoperoxide prostaglandin H(2). MPGES1 expression is induced in inflammatory diseases, and this enzyme is regarded as a potential drug target. To aid in the drug discovery effort, a simple method for determination of inhibition mechanism and potency toward both prostaglandin H(2) and glutathione (GSH) has been developed. Using an assay with thiobarbituric acid-based detection, the inhibitory effects of six MPGES1 inhibitors were evaluated. The IC(50) values obtained at three substrate (S) concentrations ([S]<K(M), [S]≈K(M), [S]>K(M)) were used to estimate inhibition modality and inhibition constant values. This facilitated strategy is a useful and general screening method to evaluate the inhibitory effects of new drug compounds.
authors.affiliation: Actar AB, Solna, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Spahiu
authors.forename: Patric
authors.initials: P
authors.lastname: Stenberg
authors.forename: Charlotte
authors.initials: C
authors.lastname: Larsson
authors.forename: Johan
authors.initials: J
authors.lastname: Wannberg
authors.forename: Mathias
authors.initials: M
authors.lastname: Alterman
authors.forename: Björn
authors.initials: B
authors.lastname: Kull
authors.forename: Natalia
authors.initials: N
authors.lastname: Nekhotiaeva
authors.forename: Ralf
authors.initials: R
authors.lastname: Morgenstern
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D005453:Fluorescence; D005978:Glutathione / Q000032:analysis; D006801:Humans; D007211:Indoles / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D008315:Malondialdehyde / Q000378:metabolism; D008962:Models, Theoretical; D058990:Molecular Targeted Therapy; D010599:Pharmacokinetics; D044262:Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D013858:Thiobarbiturates / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D004791:Enzyme Inhibitors; D005978:Glutathione; D007211:Indoles; D019746:Intramolecular Oxidoreductases; D008315:Malondialdehyde; D044262:Prostaglandin H2; D000071876:Prostaglandin-E Synthases; D013858:Thiobarbiturates; C060893:MK-886; D002722:Chlorobenzenes; C029684:thiobarbituric acid