Techniques: Recent developments in computer-aided engineering of GPCR ligands using the human adenosine A3 receptor as an example.

G-protein-coupled receptors (GPCRs) represent the largest known family of signal-transducing molecules, and convey signals for light and many extracellular regulatory molecules. GPCRs are dysfunctional or dysregulated in several human diseases and are estimated to be the targets of >40% of the drugs used in clinical medicine today. The crystal structure of rhodopsin provides the first information on the three-dimensional structure of GPCRs, which now supports homology modeling studies and structure-based drug-design approaches. In this article, we review recent work on adenosine receptors, a family of GPCRs, and, in particular, on adenosine A(3) receptor antagonists. We focus on an iterative, bi-directional approach in which models are used to generate hypotheses that are tested by experimentation; the experimental findings are, in turn, used to refine the model. The success of this approach is due to the synergistic interaction between theory and experimentation.