Estimation of relative binding free energy based on a free energy variational principle for quantitative structure activity relationship analyses

In the present study, we try to estimate values of relative binding free energy of ligands to a protein based on a free energy variational principle. Results are used for quantitative structure activity relationship (QSAR) analyses. The aim of our study is to construct a procedure free from adjustable empirical parameters and expensive computational costs, and fast enough for use in QSAR. We apply our procedure to inhibitors of dehydrofolate reductase for which values of binding free energy have been studied extensively with both experimental and theoretical techniques. We demonstrate in this paper that we can obtain fairly good values when we can categorize ligands based on structural similarity or on the Log P values of substituents. The present results indicate that our procedure is valid and applicable to QSAR analyses for drug discovery when major differences in ligand structures can be regarded as small perturbations.