A 3D model of the human A1 adenosine receptor. An evaluation of the binding free-energy with ligands.

A model of A1 adenosine receptor was built on the basis of the prediction of transmembrane helices made by PHDtopology and forcing the rough initial model over the scaffold of the rhodopsin. Only helices were accurately modeled. Several complexes between the model of the A1 receptor and some ligands were built. The binding site was hypothesized on the basis of biochemical experiments (site directed mutagenesis). Ligands were selected so that their Kis range between millimolar to nanomolar. The validation of the model was carried out performing calculations of the binding free energy between ligands and the receptor model. The free energy calculations were accomplished by using the linear free energy approximation method (LIE). We could observe that the trend of the calculated delta delta Gs (differences in binding free energies between the antagonist 2, showing the lowest Ki, and the other antagonists analyzed) agreed with the one obtained from biological data.