Abstract

G protein-coupled receptors (GPCRs) represent the largest family known of signal-transducing molecules. They convey signals for light and many extracellular regulatory molecules. GPCRs have been found to be dysfunctional/ dysregulated in a growing number of human diseases and they have been estimated to be the targets of more than 40% of the drugs used in clinical medicine today. The crystal structure of rhodopsin provides the first three-dimensional GPCR information, which now supports homology modeling studies and structure-based drug design approaches. Here, we review our recent work on adenosine receptors, a family of GPCRs and, in particular, on A3 adenosine receptor subtype antagonists. We will focus on an alternative approach to computationally explore the multi-conformational space of the antagonist-like state of the human A3 receptor. We define ligand-based homology modeling as new approach to simulate the reorganization of the receptor induced by the ligand binding. The success of this approach is due to the synergic interaction between theory and experiment.

Keywords: seven trans-membrane (7TM) bundle, Cross-Docking, Ligand-Based Homology Modeling, pyrazolotriazolopyrimidines, Y-shaped 3D-pharmacophore model