Pharmacophore based receptor modeling: the case of adenosine A3 receptor antagonists. An approach to the optimization of protein models

To design and synthesize new potent and selective antagonists of the human A(3) Adenosine Receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecular model of the receptor built by homology modeling. The alignment of the ligands proposed by Catalyst was then used to manually DOCK a set of known A(3) antagonists into the binding site, and as a result, the model was able to explain the different binding mode of very active compounds with respect to less active ones and to reproduce, with good accuracy, free energies of binding. The docking highlighted that the nonconserved residue Tyr254 could play an important role for A(3) selectivity, suggesting that a mutagenesis study on this residue could be of interest in this respect. The reliability of the whole approach was successfully tested by rational design and synthesis of new compounds.