Here we chart the quest to agonize GPR40 (FFAR1), the G protein-coupled medium to long chain free fatty acid receptor, as a possible mechanism for the treatment of Type II Diabetes Mellitus. Clinical studies indicate that partial agonists of GPR40, e.g. MK-8666, enhance glucose-dependent insulin secretion. A single crystal structure of GPR40 with MK-8666 shone a spotlight on partial agonism, and rationalized the SAR around MK-8666.

Exploring the multiple activation mechanisms of GPR40 led to the discovery of a second class of compounds, AgoPAMs. Pre-clinical studies indicate that AgoPAMs can behave both as full agonists of GPR40 and allosteric modulators of partial agonists, and can provide additional efficacy through gut-driven incretin secretion. Using only the crystal structure of the partial agonist-bound receptor for guidance for this new class of compounds proved to be misleading, and it was apparent that we needed new insights. A second crystal structure with both an AgoPAM and a partial agonist bound shone new light on the project, providing key mechanistic and SAR understandings that could guide both compound and pre-clinical study design.

In summary, structure enablement for GPR40 has provided gradual illumination of the pathway to the clinic for GPR40 agonists and has highlighted some general lessons for structure-based drug design on GPCRs along the way, most notably: that we should not be surprised when diverse ligand profiles are matched by diverse binding sites, and that extensive mutagenesis and more than one crystal structure are essential for a clearer understanding of these ubiquitous and vital receptors.