X-ray Crystallography Contributions to Drug Discovery Against Parasite

Neglected tropical diseases, including malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis, are endemic in tropical/subtropical countries and affect over 1 billion people worldwide. X-ray crystallography is crucial for drug discovery platforms, providing essential insights into the mechanism of action and inhibition of protein targets to conceive potent and selective inhibitors. To date, hundreds of parasite proteins have been identified as validated or potential targets for the development of new drugs toward neglected tropical diseases. This review focuses on the structure and the inhibition of two enzyme targets, pteridine reductase and heat shock proteins, belonging to key metabolic pathways in protozoan parasites. We summarize here the large amount of structural information that has been reported on these enzymes, providing a key contribution to the rational design of potent inhibitors. The structure-based drug discovery approach has been proven to be a powerful strategy for the identification of new treatments for neglected tropical diseases.