VORONOI MODELING - THE BINDING OF TRIAZINES AND PYRIMIDINES TO LACTOBACILLUS-CASEI DIHYDROFOLATE-REDUCTASE

Vorom is a computer-aided method of drug design which can model a biol ogical receptor give only binding data of known ligands. Using the bin ding 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 ch aracteristics of the binding site. One such model of L. casei dihydrof olate reductase was made. The model was able to predict the binding en ergies of 31 pyrimidine and triazine inhibitors out of a total set of 47, using only eight of the molecules (four pyrimidines and four triaz ines) 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 an d the geometry of the site model are also consistent with published NM R and crystallographic data.