New Opportunities in the Structure-based Design of Anti-Protozoan Agents.

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 structure-based 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.