Prediction of relative potency of ketone protease inhibitors using molecular orbital theory

Molecular orbital calculations were carried out on a series of model ketonic protease inhibitors. A comparison of the LUMO energy of the ketones in a variety of model heterocyclic ketone protease inhibitors shows a correlation with the electrophilicity of the carbonyl, and the sigma 1 experimental data. It is also observed that the more negative charge on the nitrogen atom in the heterocyclic ring the greater its potential as a hydrogen bond acceptor. The results of this study provide a simple means of predicting relative inhibitor potency and is therefore of use both to medicinal chemists designing protease inhibitors and in QSAR studies.