Towards selective lysophospholipid GPCR modulators

•We outline the importance of the lysophospholipid GPCRs as drug targets.•We highlight the challenges in developing selective modulators of these receptors.•We outline the currently available selective modulators targeting some of the receptor subtypes.•We touch on the recent structure of the Edg lipid GPCR (S1PR1), but highlight the need for a representative structure of a non-Edg-like GPCR family member.•Targeting the non-conserved allosteric binding sites of these lipid GPCRs shows particular promise for the development of selective modulators by structure-based drug design.

G-protein-coupled receptors (GPCRs) that recognize the lysophospholipids (LPLs) are grouped into two phylogenetically distinct families: the endothelial differentiation gene (Edg) and non-Edg GPCRs. Owing to their more recent identification, and hindered by a lack of selective pharmacological tools, our understanding of the functions and signaling pathways of the non-Edg GPCRs is still in its infancy. Targeting the non-conserved allosteric binding sites of the LPL GPCRs shows particular promise for the development of selective modulators by structure-based drug design. However, only one Edg GPCR (S1PR1) structure has been determined to date, and it has low sequence identity with the non-Edg GPCRs (<20%). Thus, a representative structure of a non-Edg GPCR remains a pressing objective for selective structure-based drug design. Obtaining selective modulators targeting the non-Edg receptors would help to unravel the biology behind these novel GPCRs and potentially will support therapeutic treatment of diseases such as cancer, inflammation, and neuropsychiatric disorders.