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.
Moro
Stefano
S
Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy. stefano.moro@unipd.it
Spalluto
Giampiero
G
Jacobson
Kenneth A
KA
D000818:Animals; D017076:Computer-Aided Design / Q000639:trends; D006801:Humans; D008024:Ligands; D008722:Methods; D008954:Models, Biological; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D015398:Signal Transduction / Q000502:physiology
D008024:Ligands; D043684:Receptor, Adenosine A3; D043562:Receptors, G-Protein-Coupled