Molecular modeling of adenosine receptors

Adenosine is a ubiquitous neuromodulator for which four subtypes are known (A1, A2a, A2b, and A3). Adenosine receptors (ARs) are members of the superfamily of G protein-coupled receptors. Knowledge of the 3D structure of ARs is a fundamental tool for studying how they work and for designing newer, more potent, and selective ligands. Here, we describe the procedures for modeling ARs. The starting point is represented by the resolved X-ray crystallographic structures of the A2a adenosine receptor (AA2AR) while, in the case of the other subtypes (A1, A2b, and A3), homology modeling procedures using AA2AR as a template are necessary. Minimizations and MD simulations are the computational methods used for structural refinement. The ligand-receptor interaction is studied through molecular docking simulations. The necessity of validating the obtained computational models through all of the available experimental data is outlined. Finally, the emerging importance of the homo- and heterodimerization of ARs is taken into account and a procedure for modeling a dimer is reported.