Evaluation of New Scaffolds of Myeloperoxidase Inhibitors by Rational Design Combined with High-Throughput Virtual Screening.

Aldib, Iyas; Soubhye, Jalal; Zouaoui Boudjeltia, Karim; Vanhaeverbeek, Michel; Rousseau, Alexandre; Furtmuller, Paul G.; Obinger, Christian; Dufrasne, François; Nève, Jean; Van Antwerpen, P.; Prevost, Martine

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Aldib, Iyas; Soubhye, Jalal; Zouaoui Boudjeltia, Karim et al.

2012 • In Journal of Medicinal Chemistry, 55 (16), p. 7208-7218

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Abstract :

[en] Myeloperoxidase (MPO) is a major player of the innate immune defense system of human neutrophils and catalyzes the production of strong oxidizing and halogenating antimicrobial products. Because of its role in pathogenesis of many (inflammatory) diseases, there is great interest in the development of efficient and specific inhibitors. Here, using the X-ray structure of MPO, high-throughput molecular docking of 1350000 compounds was performed. From this virtual screening process, 81 were tested for inhibition of the chlorination activity of MPO, finally ending up with eight inhibiting candidates of different chemical structures. These were tested for inhibiting MPO-mediated low-density lipoprotein oxidation and for interacting with the relevant redox intermediates of MPO. The best inhibitors were bis-2,2'-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol and 8-[(2-aminoethyl)amino]-3,7-dihydro-3-methyl-7-(3-phenoxypropyl)-1H-purine-2,6-dione. Both did not irreversibly inactivate the enzyme but efficiently trapped it in its compound II state. We discuss the mechanism of inactivation as well as pros and cons of the performed selection process.

Disciplines :

Pharmacy, pharmacology & toxicology

Author, co-author :

Aldib, Iyas

Soubhye, Jalal

Zouaoui Boudjeltia, Karim ; Université de Mons > Faculté de Médecine et de Pharmacie > FMP - Service du Doyen

Vanhaeverbeek, Michel

Rousseau, Alexandre

Furtmuller, Paul G.

Obinger, Christian

Dufrasne, François ; Université de Mons > Faculté de Médecine et de Pharmacie > Service de Chimie thérapeutique et Pharmacognosie

Nève, Jean

Van Antwerpen, P.

Prevost, Martine

Language :

English

Title :

Evaluation of New Scaffolds of Myeloperoxidase Inhibitors by Rational Design Combined with High-Throughput Virtual Screening.

Publication date :

23 August 2012

Journal title :

Journal of Medicinal Chemistry

ISSN :

0022-2623

Publisher :

American Chemical Society, United States - District of Columbia

Volume :

Issue :

Pages :

7208-7218

Research unit :

M136 - Chimie thérapeutique et Pharmacognosie

Research institute :

R550 - Institut des Sciences et Technologies de la Santé

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