Profiling GPCR binding

To identify unexpected side effects, researchers commonly screen small molecules against GPCRs, but differences in assay conditions and signal detection between receptors makes direct data comparison difficult

Randall C Willis
TEMECULA, Calif.—To identify unexpected side effects, researchers commonly screen small molecules against GPCRs, but differences in assay conditions and signal detection between receptors makes direct data comparison difficult. Scientists at Millipore addressed this problem with a cell-based GPCR function assay that relies on a common validated readout for more than 100 GPCRs. Recently, they tested the profiling platform against a dozen small molecule compounds, finding a few surprises.
 
As they described in a poster presented at the recent SBS conference, the GPCRProfiler service is based on ChemiScreen technology, which involves a mammalian expression system that relies on endogenous promiscuous G proteins to trigger calcium mobilization by all GPCRs. Similarly, signal detection relies on an endogenous calcium-release-activated calcium channel to maximize FLIPR response.
 
They tested a panel of 12 well characterized GPCR antagonists on the platform and found that while most compounds gave expected results, two compounds were unexpectedly promiscuous. H1-antagonist pyrilamine also reacted with receptor 5-HT2A, while CXCR2-specific compound SB225002 also showed activity against several histamine receptors.

Randall C Willis

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