Structural approach of M.tuberculosis phosphoserine phosphatase as drug target for the design of original inhibitors

SerB2 of Mycobacterium tuberculosis catalyzes the last step of biosynthesis
of serine in this pathogen and is involved in its virulence. Our research aims
at discovering original inhibitors of this important drug target. Our strategy
combines complementary bio-physico-chemical approaches available within
our research institute including molecular modelling, (mecano)synthesis,
protein production and purification, enzymology, crystallography,
measurments of solubility, and cellular assays. Effect of most promising
inhibitors identified in our enzymatic assays will be further tested in cellular
models (both of human cells and Mycobacterium tuberculosis) in order to
assess the selectivity and the therapeutical potential of these compounds.
Compounds under study include analogues of clofazimine and betacarboline
derivatives. Modelling approaches (pharmacophore building and
docking simulations) will be used to explain experimental enzymatic data.
This approach will further help design of new original compounds that will
be synthesized and evaluated. Structural characterization of protein-ligand
complexes by crystallography will give insight into the molecular interactions
within the binding site of the enzyme and further help to optimize our
inhibitors.