Novel bis-arylalkylamines as myeloperoxidase ...
Type de document :
Article dans une revue scientifique
PMID :
URL permanente :
Titre :
Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study
Auteur(s) :
Aldib, Iyas [Auteur]
Gelbcke, Michel [Auteur]
Soubhye, Jalal [Auteur]
Prévost, Martine [Auteur]
Furtmüller, Paul G. [Auteur]
Obinger, Christian [Auteur]
Elfving, Betina [Auteur]
Alard, Ibaa Chikh [Auteur]
Roos, Goedele [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Delporte, Cédric [Auteur]
Berger, Gilles [Auteur]
Dufour, Damien [Auteur]
Boudjeltia, Karim Zouaoui [Auteur]
Nève, Jean [Auteur]
Dufrasne, Francois [Auteur]
Van Antwerpen, Pierre [Auteur]
Gelbcke, Michel [Auteur]
Soubhye, Jalal [Auteur]
Prévost, Martine [Auteur]
Furtmüller, Paul G. [Auteur]
Obinger, Christian [Auteur]
Elfving, Betina [Auteur]
Alard, Ibaa Chikh [Auteur]
Roos, Goedele [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Delporte, Cédric [Auteur]
Berger, Gilles [Auteur]
Dufour, Damien [Auteur]
Boudjeltia, Karim Zouaoui [Auteur]
Nève, Jean [Auteur]
Dufrasne, Francois [Auteur]
Van Antwerpen, Pierre [Auteur]
Titre de la revue :
European journal of medicinal chemistry
Nom court de la revue :
Eur J Med Chem
Numéro :
123
Pagination :
746-762
Date de publication :
2016-11-10
ISSN :
1768-3254
Mot(s)-clé(s) en anglais :
Myeloperoxidase selective inhibitors
Enzyme Inhibitors
Bis-arylalkylamines derivatives
Amines
Chemistry Techniques, Synthetic
Oxidation-Reduction
Humans
Reversible inhibitors
Structure-Activity Relationship
SERT
Drug Design
Halogenation
Protein Conformation
Docking
Pharmacomodulation
Molecular Docking Simulation
Peroxidase
Kinetics
Serotonin Uptake Inhibitors
Enzyme Inhibitors
Bis-arylalkylamines derivatives
Amines
Chemistry Techniques, Synthetic
Oxidation-Reduction
Humans
Reversible inhibitors
Structure-Activity Relationship
SERT
Drug Design
Halogenation
Protein Conformation
Docking
Pharmacomodulation
Molecular Docking Simulation
Peroxidase
Kinetics
Serotonin Uptake Inhibitors
Discipline(s) HAL :
Chimie/Chimie théorique et/ou physique
Résumé en anglais : [en]
Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening ...
Lire la suite >Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 μM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).Lire moins >
Lire la suite >Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 μM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).Lire moins >
Langue :
Anglais
Établissement(s) :
CNRS
Université de Lille
Université de Lille
Équipe(s) de recherche :
Computational Molecular Systems Biology
Date de dépôt :
2020-02-12T15:11:22Z