Targeting GPR18: Structural modelling, ligand discovery, and therapeutic potential in neuroinflammatory disorders.

GPR18, a class A G protein-coupled receptor once considered an orphan with unclear links to the endocannabinoid system (ECS), is increasingly recognized as a pharmacologically relevant component of the extended ECS. Structural, pharmacological, and functional evidence increasingly support the positioning of GPR18 within the extended ECS, with closer alignment to cannabinoid receptor 2 (CB2R) than to cannabinoid receptor 1 (CB1R) at the levels of signaling, tissue distribution, and lipid-mediated pharmacology. This review provides an updated overview of GPR18 biology through distinctive analytical approaches. First, a systematic comparison between AlphaFold-predicted structures and previously published homology models refines current understanding of conserved motifs, constitutive activity determinants, and the dynamic architecture of the ligand-binding pocket. Second, literature mining combined with open-access transcriptomic and proteomic data from the Human Protein Atlas delineates GPR18 expression across human tissues and organs, revealing preferential expression in immune, vascular, and neuroglial compartments. Third, the emerging role of GPR18 in neuroinflammation is examined, exploring its potential involvement in resolution pathways, microglial responses, and neuroprotective mechanisms, in some cases through a proposed functional interplay with CB2R. Finally, in silico chemoinformatic approaches, including PLATO-based target fishing, are employed to map the broader network engaged by the main GPR18 ligands, and to explore strategies toward the design of dual GPR18/CB2R modulators. Collectively, these evidences contribute to repositioning GPR18 from an elusive orphan G protein-coupled receptor to a characterized component of the (endo)cannabinoid interactome, with emerging promise as a potential therapeutic target for neuroinflammatory and neurodegenerative disorders, pending further pharmacological and clinical validation.