Structure-based discovery of novel US28 small molecule ligands with different modes of action

Michael Lückmann, Roxana-Maria Amarandi, Natalia Papargyri, Mette Høy Jakobsen, Elisabeth Christiansen, Lars Juhl Jensen, Aurel Pui, Thue W. Schwartz, Mette M. Rosenkilde, Thomas M. Frimurer

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Abstract

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 angstrom 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 similar to 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.
Original languageEnglish
JournalChemical Biology & Drug Design
Volume89
Issue number3
Pages (from-to)289-296
ISSN1747-0277
DOIs
Publication statusPublished - 2017

Keywords

  • Drug discovery
  • G protein-coupled receptor
  • Molecular modeling
  • Virtual screening

Cite this

Lückmann, M., Amarandi, R-M., Papargyri, N., Høy Jakobsen, M., Christiansen, E., Jensen, L. J., Pui, A., Schwartz, T. W., Rosenkilde, M. M., & Frimurer, T. M. (2017). Structure-based discovery of novel US28 small molecule ligands with different modes of action. Chemical Biology & Drug Design, 89(3), 289-296. https://doi.org/10.1111/cbdd.12848