Pharmacological relationships and ligand discovery of G protein-coupled receptors revealed by simultaneous ligand and receptor clustering

Abstract

Conventional ligand and receptor similarity methods have been extensively used for exposing pharmacological relationships and drug lead discovery. They may in some cases neglect minor relationships useful for target hopping particularly against the remote family members. To complement the conventional methods for capturing these minor relationships, we developed a new method that uses a SLARC (Simultaneous Ligand And Receptor Clustering) 2D map to simultaneously characterize the ligand structural and receptor binding-site sequence relationships of a receptor family. The SLARC maps of the rhodopsin-like GPCR family comprehensively revealed scaffold hopping, target hopping, and multi-target relationships for the ligands of both homologous and remote family members. Their usefulness in new ligand discovery was validated by guiding the prospective discovery of novel indole piperazinylpyrimidine dual-targeting adenosine A2A receptor antagonist and dopamine D2 agonist compounds. The SLARC approach is useful for revealing pharmacological relationships and discovering new ligands at target family levels.