title: Discovery of highly potent microsomal prostaglandin e2 synthase 1 inhibitors using the active conformation structural model and virtual screen.
abstract: Microsomal prostaglandin E2 synthase 1 (mPGES-1) has been identified as a promising drug target due to its key role in prostaglandin biosynthesis. However, the lack of a well-characterized structure constitutes a great challenge for the development of inhibitors. Recently, we have built a model for the active conformation of mPGES-1. In the present study, the model was used for structure-based virtual screen of novel mPGES-1 inhibitors. Of the 142 compounds tested in the cell-free assay, 10 molecules are highly potent with IC50 values of single digit nanomolar and the strongest inhibition of 1.1 nM. Moreover, nine compounds showed strong activity in the human whole blood (HWB) assay with IC50 values of less than 10 μM. The lead compounds 1 and 2 showed HWB IC50 values of 0.3 and 0.7 μM which are among the most potent mPGES-1 inhibitors reported. These compounds represent new scaffolds for future development of drugs against mPGES-1.
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Shan
authors.initials: S
authors.lastname: He
authors.forename: Cong
authors.initials: C
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005449:Fluorenes / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D000071876:Prostaglandin-E Synthases; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D005449:Fluorenes; D014227:Triazines; D014230:Triazoles; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D005978:Glutathione