Tackling the complexities of orphan GPCR ligand discovery with rationally assisted approaches

Abstract Orphan G protein-coupled receptors (GPCRs) comprise ∼25% of the targetable GPCR space. Despite their pharmacotherapeutic potential, they remain understudied owing to difficulties in interrogating their physiological roles and signaling pathways. Here, we provide a compilation of the reported putative functions of all (patho)physiologically relevant Family A orphan GPCRs, and describe assays that are most applicable to ligand screening against these cryptic receptors. We then discuss the ligand discovery challenges arising from poor understanding of the orphan GPCR interactome and unaccounted-for cellular contexts, as well as unexpected effects of variations in assay conditions on signaling. We conclude by highlighting innovative computational methodologies that can be used to tackle these challenges, exemplified by successful ligand discovery for the orphans GPR68, GPR139, and GPR37L1. These computationally guided approaches broaden the range of questions that can be asked and answered in application not only to orphan GPCRs, but also to other poorly studied protein families.