Target Sites for the Design of Anti-trypanosomatid Drugs Based on the Structure of Dihydroorotate Dehydrogenase

Abstract

Trypanosomatids consist of a large group of flagellated parasitic protozoa, including parasites from the genera Leishmania and Trypanosoma, responsible for causing infections in millions of humans worldwide and for which currently no appropriate therapy is available. The significance of pyrimidines in cellular metabolism makes their de novo and salvage pathways ideal druggable targets for pharmacological intervention and open an opportunity for pharmaceutical innovation. In the current review, we discuss the merits in targeting the enzyme dihydroorotate dehydrogenase (DHODH), a flavin-dependent enzyme that catalyzes the fourth and only redox step in pyrimidine de novo biosynthesis, as a strategy for the development of efficient therapeutic strategies for trypanosomatid-related diseases.We also describe the advances and perspectives from the structural biology point of view in order to unravel the structure-function relationship of trypanosomatid DHODHs, and to identify and validate target sites for drug development.

Recombinant production, crystallization and crystal structure determination of dihydroorotate dehydrogenase fromLeishmania (Viannia) braziliensis

“…Thus, considerable attention has been paid to the structural and functional characterization of trypanosomatid DHODHs (Tryp-DHODHs), including the Trypanosoma brucei (Arakaki et al, 2008), T. cruzi (Pinheiro et al, 2008;Inaoka et al, 2008; and L. major (Feliciano et al, 2006;Cordeiro et al, 2006Cordeiro et al, , 2012 enzymes. Selective inhibitors have already been identified for TrypDHODHs (Cheleski, Rocha et al, 2010;Pinheiro et al, 2013) and meticulous analyses of protein structures have also highlighted the presence and the dynamics of five different pockets, named S1…”

Evaluation of the leishmanicidal and cytotoxic effects of inhibitors for microorganism metabolic pathway enzymes

“…The DHODH is a dimeric enzyme that catalyzes the fourth step in the de novo pyrimidine biosynthetic pathway, with one flavin mononucleotide bound to each subunit as a prosthetic group [25]. This is also the fourth and rate-limiting step in the de novo pyrimidine pathway [28]. Despite the fact that the enzymatic function of DHODH is conserved in all organisms, the enzyme protein structure is quite different in prokaryotic and eukaryotic organisms.…”

In silico target fishing and pharmacological profiling for the isoquinoline alkaloids of Macleaya cordata (Bo Luo Hui)

“…The target glycosomal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) found by C11 was a target for the development of novel chemotherapeutic agents for the treatment of Chagas disease [48]. Dihydroorotate dehydrogenase (DHODH) retrieved by C5 and C6 was related to both Leishmania infection and Trypanosoma infection [49].…”