Mp. Bradley et Gm. Crippen, VORONOI MODELING - THE BINDING OF TRIAZINES AND PYRIMIDINES TO LACTOBACILLUS-CASEI DIHYDROFOLATE-REDUCTASE, Journal of medicinal chemistry, 36(21), 1993, pp. 3171-3177
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.