title: 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.
authors.affiliation: Laboratorio de Cristalografia de Proteinas, Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, USP., Av. Cafe S/N, Monte Alegre, Ribeirao Preto, S.P. Brazil.
authors.forename: Matheus Pinto
authors.initials: MP
authors.lastname: Pinheiro
authors.forename: Flávio da Silva
authors.initials: Fda S
authors.lastname: Emery
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Nonato
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011487:Protein Conformation; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology; D014352:Trypanosomiasis / Q000188:drug therapy
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D011742:Pyrimidine Nucleotides; D014344:Trypanocidal Agents; D044925:Oxidoreductases Acting on CH-CH Group Donors