par Van Antwerpen, Pierre 
Référence 8th International Human Peroxidase Meeting (9-12 September 2013: Sydney, Australia)
Publication Non publié, 2013-09-09
Référence 8th International Human Peroxidase Meeting (9-12 September 2013: Sydney, Australia)
Publication Non publié, 2013-09-09
Communication à un colloque
| Résumé : | Myeloperoxidase (MPO) is involved in chronic inflammatory syndromes, promoting or contributing to the severity of the disease. As a consequence, pharmaceutical industries assess the contribution of MPO inhibitors in several conditions. The inhibition of MPO is peculiar as the mechanistic includes redox reaction(s) and classical ligand/target interactions. In order to understand the MPO inhibition, the rational drug design assisted by in silico tools is an interesting approach and many experiments from our laboratories emphasized its role in the discovery of MPO inhibitors.A first approach considered 5-fluorotryptamine as a starting point for the design of a new series of alkylindole molecules. Conceived in silico, the molecules were synthesized and tested on MPO. A Quantitative Structure-Activity Relationship (QSAR) has been carried out and led to molecules that inhibit MPO at the nanomolar range. However, their structure similarity with serotonin makes these molecules active on serotonin reuptake transporter. As a consequence, a second series of alkylindole molecules was assessed in silico, synthesized and tested on MPO. Modulations of the alkylindole structure have allowed synthesizing 5-fluoro-3-propylamide-indole, a more specific MPO inhibitor active at the nanomolar range.A second approach used virtual screening to discover new potential ligands for MPO. This approach was based on the high throughput docking of thousands chemical structures and led to 8 hits constituting new families of MPO inhibitors. This approach also underlined the roles of the residue Glu102 and of the stacking of aromatic rings with pyrrol of the heme, which improve the interaction ligand/target.To sum up, rational drug design is routinely and successfully used in our laboratory to conceive new MPO inhibitors and lead to a new family of N,N-methylphenolhydropyrimidine derivatives as potential MPO inhibitors. |
