Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Soubhye J,Chikh Alard I,Aldib I,Prévost M,Gelbcke M,De Carvalho A,Furtmüller PG,Obinger C,Flemmig J,Tadrent S,Meyer F,Rousseau A,Nève J,Mathieu V,Zouaoui Boudjeltia K,Dufrasne F,Van Antwerpen Pdoi
10.1021/acs.jmedchem.7b00285subject
Has Abstractpub_date
2017-08-10 00:00:00pages
6563-6586issue
15eissn
0022-2623issn
1520-4804journal_volume
60pub_type
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