Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification.
The development of myeloperoxidase (MPO) inhibitors has been conducted using flufenamic acid as a lead compound. Computational docking of the drug and its analogs in the MPO active site was first attempted. Several molecules were then synthesized and assessed using three procedures for the measurement of their inhibiting activity: (i) the taurine assay, (ii) the accumulation of compound II, and (iii) the LDL oxidation by ELISA. Most of the synthesized molecules had an activity in the same range as flufenamic acid but none of them were able to inhibit the MPO-dependent LDL oxidation. The experiments however gave some useful indications for a rational conception of MPO inhibitors.
Van Antwerpen
Pierre
P
Laboratory of Pharmaceutical Organic Chemistry, Institut de Pharmacie, Université Libre de Bruxelles, 1050 Brussels, Belgium.
Prévost
Martine
M
Zouaoui-Boudjeltia
Karim
K
Babar
Sajida
S
Legssyer
I
I
Moreau
Patrick
P
Moguilevsky
Nicole
N
Vanhaeverbeek
Michel
M
Ducobu
Jean
J
Nève
Jean
J
Dufrasne
François
F
D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005439:Flufenamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000032:analysis; D015394:Molecular Structure; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding
D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D005439:Flufenamic Acid; D009195:Peroxidase