Molecular Simulations and Drug Discovery of Adenosine Receptors

Abstract

G protein-coupled receptors (GPCRs) represent the largest family of human membrane proteins. Four subtypes of adenosine receptors (ARs), the A1AR, A2AAR, A2BAR and A3AR, each with a unique pharmacological profile and distribution within the tissues in the human body, mediate many physiological functions and serve as critical drug targets for treating numerous human diseases including cancer, neuropathic pain, cardiac ischemia, stroke and diabetes. The A1AR and A3AR preferentially couple to the Gi/o proteins, while the A2AAR and A2BAR prefer coupling to the Gs proteins. Adenosine receptors were the first subclass of GPCRs that had experimental structures determined in complex with distinct G proteins. Here, we will review recent studies in molecular simulations and computer-aided drug discovery of the adenosine receptors and also highlight their future research opportunities.

The adenosine A2A receptor in human sperm: its role in sperm motility and association with in vitro fertilization outcomes

“…Adenosine receptors, specifically the A1, A2, and A3 receptor subtypes, have been identified and successfully cloned in mammals ( 15 ). Within the A2 receptor subtype, further categorization can be made into A2A and A2B receptors based on their affinity for adenosine ( 15 ). However, under normal physiological conditions, the concentration of adenosine is insufficient to activate A2B receptors.…”

Problems and prospects for finding new pharmacological agents among adenosine receptor agonists, antagonists, or their allosteric modulators for the treatment of cardiovascular diseases

“…α5-helix G αi , which is accompanied by an outward movement of TM6 by 10.5 Å. In this case, receptor activation is accompanied by adjustments of TM7, helix 8 (H8), extracellular loops (EL), and the ligand-binding pocket [42].…”

“…During realization of cardiovascular responses, A1AR is associated with other AR subtypes: for example, it counteracts A2AR-mediated vasodilation [55]. There is evidence of interaction between A1, A2A and A2B ARs in the mechanisms of cardioprotection [17,42]. At the same time, it should be noted that the AR heteromers A1/A2A have not yet been studied in the cardiovascular system.…”

Minute-timescale simulations of G Protein Coupled Receptor A2A activation mechanism reveal a receptor pseudo-active state

“…Atomistic simulations based on molecular dynamics (MD) techniques 9,33,[42][43][44][45][46][47][48][49][34][35][36][37][38][39][40][41] have demonstrated ability in detecting dynamic properties of the receptor, including the interaction with ligands and effectors. 9,31,[41][42][43][44][45][46][47][48][49][50][33][34][35][36][37][38][39][40] . However, the long -ms -timescale and the complex allosteric network ruling GPCR activation make it elusive even to sophisticated simulation protocols.…”