Computer-aided drug design: Modeling the binding of pyrimidines and triazines to Lactobacillus casei dihydrofolate reductase.

Abstract

Voronoi binding site modeling 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 competitive, reversible inhibitors of a biological macromolecule, we can correctly predict the binding energies and conformations of other small flexible 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 (DHFR) was made which correctly predicted the experimental binding energies of 31 pyrimidine and triazine inhibitors out of a total set of 47, using data on only 8 of the molecules as input. The binding energy of methotrexate, a well known inhibitor of DHFR which is neither a pyrimidine nor a triazine, was correctly predicted. The binding mode of methotrexate predicted by the model was 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.