Molecular Dynamics Simulations of Adenosine Receptors: Advances, Applications and Trends

Adenosine receptors (ARs) are transmembrane proteins that belong to the G protein-coupled receptors (GPCRs) superfamily and mediate the biological functions of adenosine. To date, four AR subtypes are known, namely A1, A2A, A2B and A3 that exhibit different signaling pathways, tissue localization, and mechanisms of activation. Moreover, the widespread ARs and their implication in numerous physiological and pathophysiological conditions had made them pivotal therapeutic targets for developing clinically effective agents. The crystallographic success in identifying the 3D crystal structures of A2A and A1 ARs has dramatically enriched our understanding of their structural and functional properties such as ligand binding and signal transduction. This, in turn, has provided a structural basis for a larger contribution of computational methods, particularly molecular dynamics (MD) simulations, toward further investigation of their molecular properties and designing bioactive ligands with therapeutic potential. MD simulation has been proved to be an invaluable tool in investigating ARs and providing answers to some critical questions. For example, MD has been applied in studying ARs in terms of ligand-receptor interactions, molecular recognition, allosteric modulations, dimerization, and mechanisms of activation, collectively aiding in the design of subtype selective ligands. In this review, we focused on the advances and different applications of MD simulations utilized to study the structural and functional aspects of ARs that can foster the structure-based design of drug candidates. In addition, relevant literature was briefly discussed which establishes a starting point for future advances in the field of drug discovery to this pivotal group of drug targets.