Prediction of selective bioreductive anti-tumour, anti-folate activity using a modified ab initio method for calculating enzyme–inhibitor interaction energies

Abstract

Enzyme–ligand binding energies may be calculated using an ab initio molecular orbital method in which the ligand is treated fully and the enzyme is modelled by point charges. Modifications of the method are described whereby the two-electron integrals are re-used (thereby speeding up the calculations considerably) and the interaction energy is decomposed into an electrostatic energy and a polarization energy. The modified method has been used in connection with two different docking procedures, and is tested on a number of potential anti-cancer bioreductive anti-folates. The inhibitors of dihydrofolate reductase described here have been specifically designed to bind to the enzyme in their reduced form, but to have a repulsive interaction in their oxidized form. Since the reduced form would be favoured in the oxygen-deficient environment of solid tumours, the designed inhibitors should be tumour selective.