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Structure-based discovery of novel US28 small molecule ligands with different modes of action.
Lückmann, Michael; Amarandi, Roxana-Maria; Papargyri, Natalia; Jakobsen, Mette H; Christiansen, Elisabeth; Jensen, Lars J; Pui, Aurel; Schwartz, Thue W; Rosenkilde, Mette M; Frimurer, Thomas M.
Afiliación
  • Lückmann M; Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Amarandi RM; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Papargyri N; Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Jakobsen MH; Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, Iasi, Romania.
  • Christiansen E; Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Jensen LJ; Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
  • Pui A; Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Schwartz TW; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
  • Rosenkilde MM; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
  • Frimurer TM; Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, Iasi, Romania.
Chem Biol Drug Des ; 89(3): 289-296, 2017 03.
Article en En | MEDLINE | ID: mdl-27569905
The human cytomegalovirus-encoded G protein-coupled receptor US28 is a constitutively active receptor, which can recognize various chemokines. Despite the recent determination of its 2.9 Å crystal structure, potent and US28-specific tool compounds are still scarce. Here, we used structural information from a refined US28:VUF2274 complex for virtual screening of >12 million commercially available small molecule compounds. Using a combined receptor- and ligand-based approach, we tested 98 of the top 0.1% ranked compounds, revealing novel chemotypes as compared to the ~1.45 million known ligands in the ChEMBL database. Two compounds were confirmed as agonist and inverse agonist, respectively, in both IP accumulation and Ca2+ mobilization assays. The screening setup presented in this work is computationally inexpensive and therefore particularly useful in an academic setting as it enables simultaneous testing in binding as well as in different functional assays and/or species without actual chemical synthesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Receptores de Quimiocina / Bibliotecas de Moléculas Pequeñas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Chem Biol Drug Des Asunto de la revista: BIOQUIMICA / FARMACIA / FARMACOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Receptores de Quimiocina / Bibliotecas de Moléculas Pequeñas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Chem Biol Drug Des Asunto de la revista: BIOQUIMICA / FARMACIA / FARMACOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido