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

Area of Science:

• Biochemistry
• Biophysics
• Pharmacology

Background:

• Surface plasmon resonance (SPR) is crucial for studying ligand-protein interactions, particularly for low-affinity fragments in early drug discovery.
• Screening membrane proteins like G-protein-coupled receptors (GPCRs) using SPR presents biochemical challenges, especially for native receptors.

Purpose of the Study:

• To demonstrate the utility of SPR biosensors for screening ultralow molecular weight fragments against the human adenosine receptor family.
• To identify novel, biologically active binders with varying selectivity for the human adenosine 2a receptor (hA2AR).

Main Methods:

• Utilized SPR-based biosensors for high-throughput screening of fragment libraries.
• Employed ultralow molecular weight fragments (<200 Da) and the GlaxoSmithKline (GSK) kinase library.
• Focused on native/wild-type, non-thermostabilized G-protein-coupled receptors (GPCRs).

Main Results:

• Successfully screened ultralow-affinity fragments, identifying novel binders for adenosine receptors.
• Discovered compounds with a range of selectivity for the human adenosine 2a receptor (hA2AR).
• Demonstrated SPR's effectiveness as a chemical filter for small building block fragments.

Conclusions:

• SPR is a powerful tool for identifying biologically meaningful chemical entities from fragment libraries.
• SPR campaigns are highly effective in enabling drug discovery programs by filtering small molecular fragments.
• This study highlights the successful application of SPR in fragment-based drug discovery for challenging targets like adenosine receptors.