Structure-Based Design, Synthesis, and Characterization of Inhibitors of Human and <i>Plasmodium falciparum</i> Dihydroorotate Dehydrogenases

TLDR

Pyrimidine biosynthesis, particularly the dihydroorotate dehydrogenase step, is a validated drug target in humans and the malaria parasite *Plasmodium falciparum*. The authors sought to use SPROUT‑LeadOpt to improve binding of leflunomide’s active metabolite to the dihydroorotate dehydrogenases of both species. They applied the SPROUT‑LeadOpt structure‑based drug discovery platform to design and synthesize a library of optimized inhibitors, and solved co‑crystal structures of five compounds in the human enzyme’s ubiquinone cavity. The SPROUT‑designed inhibitors exhibited strong inhibitory activity against both human and parasite enzymes, validating the predictive accuracy of the optimization approach.

Abstract

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.