Surface Plasmon Resonance Screening to Identify Active and Selective Adenosine Receptor Binding Fragments

Claire Shepherd, Sean Robinson, Alice Berizzi, Laura E. J. Thompson, Louise Bird, Simone Culurgioni, Simon Varzandeh, Philip B. Rawlins, Reid H. J. Olsen (Lead / Corresponding author), Iva Hopkins Navratilova (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Surface plasmon resonance (SPR) is a widely used method to study ligand-protein interactions. The throughput and sensitivity of SPR has made it an important technology for measuring low-affinity, ultralow weight fragments (<200 Da) in the early stages of drug discovery. However, the biochemistry of membrane proteins, such as G-protein-coupled receptors (GPCRs), makes their SPR fragment screening particularly challenging, especially for native/wild-type, nonthermostabilized mutant receptors. In this study, we demonstrate the use of SPR-based biosensors to study the entire human family of adenosine receptors and present biologically active novel binders with a range of selectivity to human adenosine 2a receptor (hA2AR) from an ultralow weight fragment library and the public GlaxoSmithKline (GSK) kinase library. Thus, we demonstrate the ability of SPR to screen ultra-low-affinity fragments and identify biologically meaningful chemical equity and that SPR campaigns are highly effective "chemical filters" for screening small building block fragments that can be used to enable drug discovery programs.

Original languageEnglish
Pages (from-to)1172-1181
Number of pages10
JournalACS Medicinal Chemistry Letters
Volume13
Issue number7
Early online date6 Jun 2022
DOIs
Publication statusPublished - 14 Jul 2022

Keywords

  • GPCRs
  • fragments
  • screening
  • surface plasmon resonance

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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