Projets par an
Résumé
Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen’s serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants (Ki) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited M. tuberculosis growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2.
langue originale | Anglais |
---|---|
Numéro d'article | 415 |
Nombre de pages | 17 |
journal | Molecules |
Volume | 25 |
Numéro de publication | 2 |
Les DOIs | |
Etat de la publication | Publié - 19 janv. 2020 |
Empreinte digitale
Examiner les sujets de recherche de « Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase ». Ensemble, ils forment une empreinte digitale unique.Projets
- 2 Terminé
-
Approche structurale de la phosphosérine phosphatase de M.tuberculosis en vue de la conception d’inhibiteurs à intérêt thérapeutique
Pierson, E. (Responsable du Projet) & Wouters, J. (Promoteur)
1/10/18 → 30/09/19
Projet: Recherche
-
Structural and inhibition study of SerB2 (Mycobacterium tuberculosis phosphoserine phosphatase)
Haufroid, M. (Chercheur) & Wouters, J. (Promoteur)
1/09/16 → 31/08/22
Projet: Projet de thèse