An evaluation of automated in silico ligand docking of amino acid ligands to Family C G-protein coupled receptors Original Research Article

Family C G-protein coupled receptors (GPCRs) consist of the metabotropic glutamate receptors (mGluRs), the calcium-sensing receptor (CaSR), the T1R taste receptors, the GABAB receptor, the V2R pheromone receptors, and several chemosensory receptors. A common feature of Family C receptors is the presence of an amino acid binding pocket. The objective of this study was to evaluate the ability of the automatic docking program FlexX to predict the favored amino acid ligand at several Family C GPCRs. The docking process was optimized using the crystal structure of mGluR1 and the 20 amino acids were docked into homology models of the CaSR, the 5.24 chemosensory receptor, and the GPRC6A amino acid receptor. Under optimized docking conditions, glutamate was docked in the binding pocket of mGluR1 with a root mean square deviation of 1.56 angstroms from the co-crystallized glutamate structure and was ranked as the best ligand with a significantly better FlexX score compared to all other amino acids. Ligand docking to a homology model of the 5.24 receptor gave generally correct predictions of the favored amino acids, while the results obtained with models of GPRC6A and the CaSR showed that some of the favored amino acids at these receptors were correctly predicted, while a few other top scoring amino acids appeared to be false positives. We conclude that with certain caveats, FlexX can be successfully used to predict preferred ligands at Family C GPCRs.