Voronoi modeling: the binding of triazines and pyrimidines to L. casei dihydrofolate reductase

Vorom is a computer-aided method of drug design which can model a biological receptor given only binding data of known ligands. Using the binding energies of known competitive, reversible ligands of a biological macromolecule, vorom can make predictions about the binding energies and conformations of other small molecules binding to that receptor as well as provide information about the geometry and physicochemical characteristics of the binding site. One such model of L. casei dihydrofolate reductase was made. The model was able to predict the binding energies of 31 pyrimidine and triazine inhibitors out of a total set of 47, using only eight of the molecules (four pyrimidines and four triazines) as input. The binding energy of methotrexate, which is neither a pyrimidine nor a triazine, was correctly predicted. The binding mode of methotrexate predicted by vorom is entirely consistent with known X-ray data. The predicted binding modes of the pyrimidine inhibitors and the geometry of the site model are also consistent with published NMR and crystallographic data.