2. Academic Validation
  3. Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

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

  • J Med Chem. 2017 Aug 10;60(15):6563-6586. doi: 10.1021/acs.jmedchem.7b00285.
Jalal Soubhye 1,  Ibaa Chikh Alard 2,  Iyas Aldib 1,  Martine Prévost 3,  Michel Gelbcke 1,  Annelise De Carvalho 4,  Paul G Furtmüller 5,  Christian Obinger 5,  Jörg Flemmig 6,  Sara Tadrent 1,  Franck Meyer 7,  Alexandre Rousseau 8,  Jean Nève 1,  Véronique Mathieu 4,  Karim Zouaoui Boudjeltia 8,  François Dufrasne 1,  Pierre Van Antwerpen 1 9
Affiliations

Affiliations

  • 1 Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
  • 2 Laboratoire de Pharmacie Galénique et Biopharmacie, Faculté de Pharmacie, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
  • 3 Laboratoire de Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
  • 4 Laboratoire de Cancérologie et Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
  • 5 Department of Chemistry, BOKU-University of Natural Resources and Life Sciences , 1190 Vienna, Austria.
  • 6 Institute for Medical Physics and Biophysics, Medical Faculty, University of Leipzig , Haertelstrasse 16-18, 04107 Leipzig, Germany.
  • 7 Laboratory of Biopolymers and Supramolecular Nanomaterials, Faculty of Pharmacy, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
  • 8 Laboratory of Experimentral Medicine, CHU Charleroi, A. Vsale Hospital, and Université Libre de Bruxelles , 6110 Montigny-le-Tilleul, Belgium.
  • 9 Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
PMID: 28671460 DOI: 10.1021/acs.jmedchem.7b00285
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.

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