Class C G protein-coupled receptors encompass a range of promising
therapeutic targets for a variety of diseases, yet to date only two members of this
sub-family of GPCRs have been drugged. Recent advances in structural biology
have revealed the X-ray crystallographic structures of allosteric ligands bound to
two Class C metabotropic glutamate (mGlu) receptors, mGlu1 and mGlu5. Herein,
we review how this information can be leveraged to help understand some of the
historical challenges of mGlu receptor allosteric modulator drug discovery, and
discuss how the structural enablement can be prospectively used for structurebased
drug discovery approaches across Class C GPCR targets in general.
Keywords: Allosteric, CNS, Crystallography, Glutamate, GPCR, Modulator.
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