Structure-based discovery of inhibitors of microsomal prostaglandin E 2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: Promising hits for the development of new anti-inflammatory agents

摘要

Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 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 IC50 value of 3.2 μ-M, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC50 = 0.4 μ-M).