Evaluation of new scaffolds of myeloperoxidase inhibitors by rational design combined with high-throughput virtual screening.
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.
Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Iyas
I
Aldib
Jalal
J
Soubhye
Karim
K
Zouaoui Boudjeltia
Michel
M
Vanhaeverbeek
Alexandre
A
Rousseau
Paul G
PG
Furtmüller
Christian
C
Obinger
Francois
F
Dufrasne
Jean
J
Nève
Pierre
P
Van Antwerpen
Martine
M
Prévost
D020134:Catalytic Domain; D062126:Databases, Chemical; D015195:Drug Design; D054879:Halogenation; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000737:chemistry; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
D008077:Lipoproteins, LDL; D011687:Purines; D011743:Pyrimidines; D009195:Peroxidase