Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 60; no. 15; pp. 6563 - 6586
Main Authors:	Soubhye, Jalal, Chikh Alard, Ibaa, Aldib, Iyas, Prévost, Martine, Gelbcke, Michel, De Carvalho, Annelise, Furtmüller, Paul G, Obinger, Christian, Flemmig, Jörg, Tadrent, Sara, Meyer, Franck, Rousseau, Alexandre, Nève, Jean, Mathieu, Véronique, Zouaoui Boudjeltia, Karim, Dufrasne, François, Van Antwerpen, Pierre
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 10-08-2017
Subjects:	Benzimidazoles - chemical synthesis Benzimidazoles - pharmacology Benzimidazoles - toxicity Cell Line Databases, Chemical Drug Design Drug Evaluation, Preclinical Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Enzyme Inhibitors - toxicity Glutamic Acid - chemistry Glutamine - chemistry Guanidines - chemical synthesis Guanidines - pharmacology Guanidines - toxicity Humans Hydrogen Peroxide - chemistry Kinetics Lactoperoxidase - antagonists & inhibitors Lipoproteins, LDL - chemistry Models, Chemical Molecular Docking Simulation Neutrophils - drug effects Neutrophils - metabolism Oxidation-Reduction Peroxidase - antagonists & inhibitors Quinazolines - chemical synthesis Quinazolines - pharmacology Quinazolines - toxicity Stereoisomerism
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Summary:	The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.7b00285