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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase-ligand complexes following further refinement

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Autor(es):
Bueno, Renata [1] ; Dawson, Alice [1] ; Hunter, William N. [1]
Número total de Autores: 3
Afiliação do(s) autor(es):
[1] Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Dundee DD1 5EH - Scotland
Número total de Afiliações: 1
Tipo de documento: Artigo Científico
Fonte: ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS; v. 75, n. 3, p. 148-152, MAR 2019.
Citações Web of Science: 0
Resumo

The enzymes involved in folate metabolism are key drug targets for cell-growth modulation, and accurate crystallographic structures provide templates to be exploited for structure-based ligand design. In this context, three ternary complex structures of human methylenetetrahydrofolate dehydrogenase/cyclohydrolase have been published {[}Schmidt et al. (2000), Biochemistry, 39, 6325-6335] and potentially represent starting points for the development of new antifolate inhibitors. However, an inspection of the models and the deposited data revealed deficiencies and raised questions about the validity of the structures. A number of inconsistencies relating to the publication were also identified. Additional refinement was carried out with the deposited data, seeking to improve the models and to then validate the complex structures or correct the record. In one case, the inclusion of the inhibitor in the structure was supported and alterations to the model allowed details of enzyme-ligand interactions to be described that had not previously been discussed. For one weak inhibitor, the data suggested that the ligand may adopt two poses in the binding site, both with few interactions with the enzyme. In the third case, that of a potent inhibitor, inconsistencies were noted in the assignment of the chemical structure and there was no evidence to support the inclusion of the ligand in the active site. (AU)

Processo FAPESP: 16/16038-5 - Exploração de estratégias de triagem para identificar inibidores de n°,5 N10: metilenotetrahidrofolato desidrogenase-ciclohidrolase de Xanthomonas albilineans
Beneficiário:Renata Vieira Bueno
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado