Homology Modeling and Structure Validation of the Adenosine A1 Receptor

A three dimensional structure model of the adenosine A(1) receptor was built using homology modeling. The antagonist DPCPX was docked into the model protein to form a receptor-ligand complex. A molecular dynamics simulation over 5 ns was performed for this complex. We selected 12 protein structures, including the average structure obtained from the last 2 ns of the simulation and 11 frames extracted after equilibration for the study. A database comprising 52 active antagonists and 1000 decoys was then docked into the 12 protein models using DOCK, VINA, and GOLD software packages and these molecules were ranked by their docking scores. The best model protein with the highest enrichment factor (EF) and the largest area under the ROC (AU-ROC) was chosen for further study. The results from the enrichment factor at 10% of the ranked database (EF10) and AU-ROC calculations indicate that GOLD is the best virtual screening software for the adenosine A1 receptor. GOLD docking results suggest that optimized adenosine A(1) receptor protein structures, Favg and F5, can be used for virtual screening and for novel design to discover more potent antagonists.