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DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts.
Froes, Thamires Quadros; Zapata, Luana Carlos Campisano; Akamine, Juliana Sayuri; Castilho, Marcelo Santos; Nonato, Maria Cristina.
Afiliação
  • Froes TQ; Laboratorio de Cristalografia de Proteinas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto - USP, Av. do Cafe, s/n - Vila Monte Alegre, Ribeirao Preto-SP, 14040-900, Brazil.
  • Zapata LCC; Laboratorio de Cristalografia de Proteinas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto - USP, Av. do Cafe, s/n - Vila Monte Alegre, Ribeirao Preto-SP, 14040-900, Brazil.
  • Akamine JS; Laboratorio de Cristalografia de Proteinas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto - USP, Av. do Cafe, s/n - Vila Monte Alegre, Ribeirao Preto-SP, 14040-900, Brazil.
  • Castilho MS; Faculdade de Farmacia da Universidade Federal da Bahia, Av. Barao de Jeremoabo s/n Ondina, Salvador-BA, 40170-115, Brazil.
  • Nonato MC; Laboratorio de Cristalografia de Proteinas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto - USP, Av. do Cafe, s/n - Vila Monte Alegre, Ribeirao Preto-SP, 14040-900, Brazil.
Curr Top Med Chem ; 21(23): 2134-2154, 2021.
Article em En | MEDLINE | ID: mdl-34348625
BACKGROUND: Dihydroorotate dehydrogenase (DHODH) has long been recognized as an important drug target for proliferative and parasitic diseases, including compounds that exhibit trypanocidal action and broad-spectrum antiviral activity. Despite numerous and successful efforts in structural and functional characterization of DHODHs, as well as in the development of inhibitors, DHODH hot spots remain largely unmapped and underexplored. OBJECTIVE: This review describes the tools that are currently available for the identification and characterization of hot spots in protein structures and how freely available webservers can be exploited to predict DHODH hot spots. Moreover, it provides for the first time a review of the antiviral properties of DHODH inhibitors. METHODS: X-ray structures from human (HsDHODH) and Trypanosoma cruzi DHODH (TcDHODH) had their hot spots predicted by both FTMap and Fragment Hotspot Maps web servers. RESULTS: FTMap showed that hot spot occupancy in HsDHODH is correlated with the ligand efficiency (LE) of its known inhibitors, and Fragment Hotspot Maps pointed out the contribution of selected moieties to the overall LE. The conformational flexibility of the active site loop in TcDHODH was found to have a major impact on the druggability of the orotate binding site. In addition, both FTMap and Fragment Hotspot Maps servers predict a novel pocket in TcDHODH dimer interface (S6 site). CONCLUSION: This review reports how hot spots can be exploited during hit-to-lead steps, docking studies or even to improve inhibitor binding profile and by doing so using DHODH as a model, points to new drug development opportunities.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Desenvolvimento de Medicamentos / Di-Hidro-Orotato Desidrogenase Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Curr Top Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Brasil País de publicação: Emirados Árabes Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Desenvolvimento de Medicamentos / Di-Hidro-Orotato Desidrogenase Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Curr Top Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Brasil País de publicação: Emirados Árabes Unidos