Structure-based Discovery of Novel US28 Small Molecule Ligands With Different Modes of Action

Chem Biol Drug Des. 2017 Mar;89(3):289-296. doi: 10.1111/cbdd.12848. Epub 2016 Sep 28.

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 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.

Keywords: G protein-coupled receptor; drug discovery; molecular modeling; virtual screening.

Publication types

  • Editorial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells / drug effects
  • Calcium / metabolism
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • High-Throughput Screening Assays / methods
  • Humans
  • Ligands
  • Models, Molecular
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Receptors, Chemokine / agonists
  • Receptors, Chemokine / chemistry*
  • Receptors, Chemokine / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Viral Proteins / agonists
  • Viral Proteins / chemistry*
  • Viral Proteins / metabolism

Substances

  • Ligands
  • Piperidines
  • Receptors, Chemokine
  • Small Molecule Libraries
  • US28 receptor, Cytomegalovirus
  • VUF 2274
  • Viral Proteins
  • Calcium