Discovery of novel, non-acidic mPGES-1 inhibitors by virtual screening with a multistep protocol

Stefan M Noha; Katrin Fischer; Andreas Koeberle; Ulrike Garscha; Oliver Werz; Daniela Schuster

doi:10.1016/j.bmc.2015.05.045

Discovery of novel, non-acidic mPGES-1 inhibitors by virtual screening with a multistep protocol

Bioorg Med Chem. 2015 Aug 1;23(15):4839-4845. doi: 10.1016/j.bmc.2015.05.045. Epub 2015 Jun 1.

Authors

Stefan M Noha¹, Katrin Fischer², Andreas Koeberle², Ulrike Garscha², Oliver Werz², Daniela Schuster³

Affiliations

¹ Computer Aided Molecular Design (CAMD) Group, Institute of Pharmacy/Pharmaceutical Chemistry, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria.
² Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
³ 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.

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).

Keywords: 3D pharmacophore; Inflammation; Kruskal–Wallis test; Virtual screening; mPGES-1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Line, Tumor
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Humans
Intramolecular Oxidoreductases / antagonists & inhibitors*
Intramolecular Oxidoreductases / metabolism
Microsomes / enzymology
Molecular Docking Simulation
Prostaglandin-E Synthases
Protein Binding
Protein Structure, Tertiary

Substances

Enzyme Inhibitors
Intramolecular Oxidoreductases
PTGES protein, human
Prostaglandin-E Synthases