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, 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.