Finding ligands for G protein-coupled receptors based on the protein–compound affinity matrix

We developed a novel method of identifying new active ligands based on information related to known active compounds using protein–compound docking simulations, even when the tertiary structure of the actual target receptor protein is unknown. This method was used to find ligands of G protein-coupled receptors (GPCRs), i.e., agonists and antagonists of histamine, adrenaline, serotonin and dopamine receptors. The principal component analysis (PCA) method was applied to the protein–compound affinity matrix, which was given by thorough docking calculations between sets of many protein pockets and chemical compounds. The set of protein pockets did not necessary include the target protein. Each compound was depicted as a point in the PCA space. Compounds in a sphere, whose center was set to the known active compound in the multi-dimensional PCA space or to the average position of several known active compounds, were selected as candidate-hit compounds. Our method was found to be effective for finding the ligands of GPCRs based on known native ligands, even when only the soluble protein structures were used in the docking simulations.