The angiotensin II receptors AT1R and AT2R are the key components of the renin-angiotensin-aldosterone system. While AT1R is important for the blood pressure control, the less studied AT2R has a variety of reported neurological effects including regulation of growth and sensitivity of neurons. As such, AT2R inhibition has emerged as a potential target for chronic neuropathic pain, with a selective AT2 antagonist EMA401 as a clinical candidate in Phase II studies. However, the mechanisms of action of AT2R ligands remain enigmatic, and ligands with improved potency and selectivity profiles are needed to probe this function in vivo.

We have recently solved crystal structures of human AT1R and AT2R complexes with corresponding ligands and drug candidates, highlighting unusual conformational features of these receptors. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity, providing insights into the molecular basis of the distinct functions of the two angiotensin receptors1,2. Building upon this structural information, we have performed initial virtual screening for new AT2 ligands, which has revealed several novel lead-like chemotypes with high ligand efficiency and AT2 selectivity. These results provide a proof of concept for establishing a structure-based ligand discovery platform for AT2R antagonists as in vivo probes and potential leads for addiction-free neuropathic chronic pain therapies.