Adenosine A1 receptor (A1AR) is a G-protein-coupled receptor (GPCR) that has served as an important drug target. 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. Recently, a new PAM of the A1AR has been discovered to display in vivo analgesic efficacy and modulate elevated endogenous ADO that occurs in rat spinal cord as a consequence of neuropathic pain. However, binding of the PAM hardly changes the structure of active adenosine-Gi protein-bound A1AR as determined using cryo-Electron Microscopy. In this context, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method to decipher the allosteric modulation mechanism of the new PAM. Microsecond GaMD simulations revealed that binding of the PAM greatly reduced the dynamic flexibility of the A1AR and stabilized adenosine binding in the active A1AR-Gi protein complex. Therefore, the GaMD simulations have provided important insights into the dynamic mechanism of A1AR allosteric modulation, which shall greatly facilitate allosteric drug design targeting A1AR and other GPCRs.

Dynamic mechanism of allosteric modulation of adenosine A1 receptor

ACS Fall 2021

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