Novel human mPGES-1 inhibitors identified through structure-based virtual screening

Bioorganic & Medicinal Chemistry
Adel HamzaChang-Guo Zhan

Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase after exposure to pro-inflammatory stimuli and, therefore, represents a novel target for therapeutic treatment of acute and chronic inflammatory disorders. It is essential to identify mPGES-1 inhibitors with novel scaffolds as new leads or hits for the purpose of drug design and discovery that aim to develop the next-generation anti-inflammatory drugs. Herein we report novel mPGES-1 inhibitors identified through a combination of large-scale structure-based virtual screening, flexible docking, molecular dynamics simulations, binding free energy calculations, and in vitro assays on the actual inhibitory activity of the computationally selected compounds. The computational studies are based on our recently developed three-dimensional (3D) structural model of mPGES-1 in its open state. The combined computational and experimental studies have led to identification of new mPGES-1 inhibitors with new scaffolds. In particular, (Z)-5-benzylidene-2-iminothiazolidin-4-one is a promising novel scaffold for the further rational design and discovery of new mPGES-1 inhibitors. To our best knowledge, this is the first time a 3D structural model of the open...Continue Reading

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Citations

Dec 27, 2011·Journal of Computer-aided Molecular Design·Traian SuleaEnrico O Purisima
Apr 11, 2012·Journal of Chemical Information and Modeling·Adel HamzaChang-Guo Zhan
Jan 31, 2013·Journal of Natural Products·Maoquan ZhouJon S Thorson
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Jan 23, 2016·Journal of Medicinal Chemistry·Andreas KoeberleOliver Werz
Dec 23, 2016·Medicinal Research Reviews·Catarina Pereira-LeiteSalette Reis
Mar 19, 2014·Journal of Chemical Information and Modeling·Adel HamzaKonstantin V Korotkov
Mar 3, 2017·Journal of Medicinal Chemistry·Ewgenij ProschakDaniel Merk
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Sep 17, 2013·PloS One·Virginie Y MartinyMaria A Miteva
Jul 16, 2014·Medicinal Research Reviews·Malkeet Singh BahiaPragati Silakari
Mar 5, 2019·Anti-cancer Agents in Medicinal Chemistry·Bahadır Bülbül, İlkay Küçükgüzel
Jul 11, 2017·Bioorganic & Medicinal Chemistry Letters·Ziyuan ZhouChang-Guo Zhan

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