Structure-based discovery of positive allosteric modulators of the A₁ adenosine receptor.

ABSTRACT: Allosteric modulation of G protein-coupled receptors (GPCRs) is an exciting strategy for developing new therapeutic agents, and it has several advantages over more commonly used orthosteric drugs. Recently determined GPCR structures have revealed allosteric pockets facing the lipid bilayer, enabling rational drug design. Here, we develop a virtual screening strategy to discover ligands of extrahelical binding pockets and apply this approach to the adenosine A₁ receptor (A₁R). The A₁R is a high-value therapeutic target for ischemia-reperfusion injury and chronic neuropathic pain. Developing effective A₁R therapeutics remains challenging due to high structural conservation across orthosteric binding sites and on-target unwanted effects stimulated b

SUBMITTER: Nguyen ATN 

PROVIDER: S-EPMC12280925 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature