Since the recent renaissance of phenotypic screening in the field of protozoan
drug discovery, is there still an opportunity for the structure-based design of
new anti-protozoan agents? Target-based approaches should be used in parallel to
phenotypic screening to strengthen the pipeline of anti-protozoan agents. We give
an overview of the protozoan drug discovery landscape highlighting four protein
targets of interest: cytochrome bc1, dihydroorotate dehydrogenase, dihydrofolate
reductase and calcium-dependent protein kinase 1. We discuss recent structurebased
design efforts to inhibit these targets, reviewing their crystal structures and
their ability to accommodate potent and selective compounds. Finally, we discuss
future opportunities to apply structure-based methods to promising molecular targets
within protozoan parasites discovered using chemical genomics.
Keywords: Apicomplexan drug discovery, CDPK1, Cytochrome bc1, DHFR, DHODH, Structure-based design.
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