Johan Wouters, donnera une conférence « Strategies to develop inhibitors of Mycobacterium tuberculosis phosphoserine phosphatase, a potential drug target » le Mercredi 3 Avril à 10h en salle Marie Curie.
Strategies to develop inhibitors of Mycobacterium tuberculosis phosphoserine phosphatase, a potential drug target.
Johan Wouters
Chemistry Department – UNamur – Belgium
Phosphoserine phosphatases catalyze the removal of the phosphate group of O-phospho-L-Serine in the last step of the biosynthesis of L-Serine (L-Ser).
Mycobacterium tuberculosis phosphoserine phosphatase, MtSerB2, is of interest as a new antituberculosis target due to its essential metabolic role in L-Serine biosynthesis and effector functions in infected cells.
The identification, by a screening approach, of original trisubstituted harmine derivatives as inhibitors of MtSerB2 will be presented. An alternative fragment-based drug design will also be described. This approach relies on a biophysical screening cascade (DSF, Ligand-based NMR, High concentration enzymatic assay) combined with crystallography and modelling (docking) approaches.
MtSerB2 is regulated through an oligomeric transition induced by L-Ser that could serve as a basis for the design of selective allosteric inhibitors. A structural, biophysical, and enzymological characterization of MtSerB2 oligomerization in the presence and absence of L-Ser will be presented. I will show that MtSerB2 coexists in dimeric, trimeric, and tetrameric forms of different activity levels interconverting through a conformationally flexible monomeric state, which is not observed in two near-identical mycobacterial orthologs. This morpheein behavior exhibited by MtSerB2 lays the foundation for future allosteric drug discovery and provides a starting point to the understanding of its peculiar multifunctional moonlighting properties.
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Haufroid, M. et al. Targeting the phosphoserine phosphatase MtSerB2 for tuberculosis drug discovery, an hybrid knowledge based /fragment based approach. Eur. J. Med. Chem. 245, 114935 (2023).
Pierson, E. et al. A morpheein equilibrium regulates catalysis in phosphoserine phosphatase SerB2 from Mycobacterium tuberculosis. Commun Biol. 6: 1024 (2023).
Informations : Adèle Laurent