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

Abstract

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic inflammatory diseases. Because of the deleterious effects of circulating MPO released from phagocytosing neutrophils, there is a great interest in the development of new efficient and specific inhibitors. It has been demonstrated that the interaction between the inhibitor and the active site is not the only key factor playing a role in the inhibition. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening combined to drug-likeness filters. Starting from a set of 727,842 compounds, 30 molecules were selected by this virtual method and tested for inhibition of the chlorination activity of MPO. Twelve out of 30 compounds were found to have an IC50 less than 5 µM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (Zinc1) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (Zinc3) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that Zinc1 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration. Pharmacomodulation has been performed to optimize the activity of Zinc1.

On the Clinical Pharmacology of Reactive Oxygen Species

“…Besides flavonoids, other natural compounds showed good activity against MPO, including ursolic acid, eugenol (Narasimhulu and Vardhan, 2015), and harmaline (Bensalem et al, 2014). Random and rational screening of non-anti-inflammatory drugs revealed that metoclopramide, hydralazine (Soubhye et al, 2017), and paroxetine (Soubhye et al, 2014) are potent MPO inhibitors. In vivo experiments have disclosed that different tryptamine compounds have an extensive therapeutic index as promising candidates for antiinflammation.…”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…As part of a study to identify new antibacterials that inhibit bacterial translation, an ethoxy analogue ( 545 ) of 543 was identified as a reasonable antibacterial with no inhibition of protein synthesis . Similarly, compound 546 , along with a broad range of compounds including primaquine (MMV000023, 547 ), was found to be an inhibitor of the heme‐contacting myeloperoxidase (MPO), which plays a role in human immunity, while 548 (related to TPR inhibitor 48 ) was found to inhibit the tumour‐promoting transcription factor 3 (STAT3) . Interestingly, while MPO production is enhanced during P. falciparum infection, data acquired by Jacobs and co‐workers indicated that suppression of MPO function accelerates parasite clearance in a mouse model of P. yoelii malaria …”

A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019)

“…The key role of MPO in atherosclerosis is the oxidative modification of LDL. These data attracted more attention to the inhibitors of this enzyme, and such strategy might be helpful for treating and/or preventing atherosclerosis and other inflammatory diseases [91].…”

“…By the exception to AZD4831, all the inhibitors which passed to clinical trials have an activity at µM range that activity that appears to be insufficient to be able to reduce the deleterious effects of MPO. In fact, the in vitro test of the inhibition of the MPO-based oxidation of LDL has shown that only the compounds which have an activity at low nM range can inhibit the formation of MoxLDL [64,67,91]. Therefore, potent reversible inhibitors may be a good choice to discover novel therapeutic interventions for atherosclerotic cardiovascular and other chronic syndromes.…”