When searching for new ligands for a receptor drug target, having some idea of where to start, such as the structure of a natural ligand, can be very useful. But with 'orphan' G-protein-coupled receptors (GPCRs), such clues are, by definition, unavailable. Help could be at hand though in the structures of known ligands for other GPCRs, as highlighted in a recent study by Bondensgaard and colleagues reported in the Journal of Medicinal Chemistry.

The recurring presence of particular structural fragments in ligands for several GPCRs — so-called privileged structures — was first noted more than a decade ago, and has been widely used since to aid in the design of libraries for GPCR screening, with some notable successes in identifying high-affinity ligands. But why particular structural fragments can be the basis for ligands at different GPCRs is not certain, and it was this question that the authors set out to investigate.

As put forward by the authors, one potential explanation for the presence of a privileged structure in ligands for a range of GPCRs is that each of those GPCRs has a region in its ligand-binding pocket that is complementary to the privileged structure. To test this idea, they took three pairs of ligands for widely differing class A GPCRs — with each ligand pair sharing a particular privileged structure — and computationally docked them into models of the GPCRs they bind to. For each pair of ligands, analysis of the ligand–receptor complexes revealed that the nature of the part of the ligand-binding pocket that interacts with the privileged structure was conserved between the two complexes, confirming the authors' hypothesis. Consideration of the receptor interactions made by the 'nonprivileged' parts of the ligands suggested that these were responsible for receptor selectivity towards the ligands.

So, one approach to ligand discovery for other GPCRs in class A (the largest GPCR class, members of which are thought to share the same binding-pocket position) could be to analyse the receptor binding pocket to see whether a particular privileged-structure-binding region is present and, if so, to design a screening library incorporating this privileged structure. This approach could clearly be particularly valuable for accelerating the discovery of modulators of orphan GPCRs. One problem, however, is that the limited number of privileged structures known at present means that there could be intellectual property issues related to their use, so there is a need to identify new such fragments.