Methods: Protein X-ray crystallography, Computational medicinal chemistry and Enzyme assay approaches was used to conduct large-scale screening of a chemical library.
Results: The resulting hits were compounds possessing different structural scaffolds, which potently inhibited TGK up to 50 nM IC50 values. Interestingly, a number of the inhibitors caused the expected improvement in the potency of AF against trypanosome cells, causing a shift in trypanocidal activity of AF (IC50) from nanomolar to picomolar concentrations (P<0.05). Remarkably, one of the inhibitors was identified as a dual inhibitor of TGK and TAO. The complex structures of both enzymes with the inhibitors have been determined, providing a platform for further refinement of the trypanocidal potencies by structure-activity relationship studies.
Conclusion: We have utilized rational design approach to identify novel trypanocidal compounds that may be used for the design of new class of anti-trypanosomal drugs for African trypanosomiasis.
E. O. Balogun,
T. Shiba, None
Y. I. Watanabe, None
A. Moore, None
S. Harada, None
K. Kita, None