Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, 
including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate 
dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine 
biosynthesis pathway, is a well-characterized target for chemotherapeutical 
intervention. In this study, we have applied SPROUT-LeadOpt, a software package 
for structure-based drug discovery and lead optimization, to improve the binding 
of the active metabolite of the anti-inflammatory drug leflunomide to the target 
cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following 
synthesis of a library of compounds based upon the SPROUT-optimized molecular 
scaffolds, a series of inhibitors generally showing good inhibitory activity was 
obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal 
structures of five of these SPROUT-designed inhibitors bound in the ubiquinone 
binding cavity of the human dihydroorotate dehydrogenase are also analyzed.