The evolution of GPCR pharmacology is far from over. Researchers have made a number of exciting and relevant discoveries in the past decade, and these have already begun to make important contributions to GPCR drug discovery.
No single topic in the GPCR world, however, currently generates more justified excitement than allosteric modulation, which has already yielded two marketed drugs and promises many more, some with capabilities, that have been so far, inaccessible. Because they do not compete with GPCRs’ natural ligands, allosteric modulators have the potential to be effective at lower, safer doses vis-à-vis orthosteric modulators. Allosteric modulators have already been identified for 34 GPCR types and subtypes. In the next seven or eight years, we may see that the majority of novel GPCR-targeted drugs act via allosteric modulation as opposed to orthosteric.
There is one research advance which has, arguably, the greatest potential for advancing GPCR pharmacology. Until last year, drug discovery scientists had available to them only a single, high-resolution x-ray crystallographic structure of a GPCR, rhodopsin, which is atypical from a drug discovery perspective.
Barriers have now been broken, and two GPCR structures, with characteristics placing them in the mainstream of commercial pharmacology interest, have become available. This confers the ability to rationally target GPCRs as opposed to running random high-throughput screens to design molecules—a development that has heralded a new era in GPCR structure-based drug design.