Mechanism of Allosteric Modulator Binding to the Adenosine A1 Receptor

Abstract

The adenosine A1 receptor (A1AR) is a key G-protein-coupled receptor (GPCR) that has served as a therapeutic target for treating cardiovascular and neurological diseases. Activation of the A1AR is able to protect the myocardium against ischemia-reperfusion injury and reduce neuropathic pain. In contrast to traditional agonists that often cause off-target side effects, positive allosteric modulators (PAMs) that increase the receptor responsiveness to endogenous adenosine in local regions are promising selective drug candidates of the A1AR. However, the binding modes of PAMs in the A1AR and mechanism of the receptor allosteric modulation remain unclear. Here, all-atom computer simulations using the robust Gaussian accelerated molecular dynamics (GaMD) method are performed to capture spontaneous binding of prototypical PAMs to the A1AR. The GaMD simulations allow free energy calculations to identify low-energy binding modes of the PAMs in the receptor. The predicted binding modes are consistent with previous mutation and binding assay experiments. These results provide important insights into the mechanism of A1AR allostery at an atomistic level. The work will be also useful for future computer-aided drug design efforts targeting the A1AR and other GPCRs.