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

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• 作者：Iyas Aldib ; Jalal Soubhye ; Karim Zouaoui Boudjeltia ; Michel Vanhaeverbeek ; Alexandre Rousseau ; Paul G. Furtm眉ller ; Christian Obinger ; Francois Dufrasne ; Jean N猫ve ; Pierre Van Antwerpen ; Martine Pr茅vost
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7208-7218
• 全文大小：539K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

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鈥?[(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.