A comparison of computer aided drug design methods for calculating relative binding affinities of COX-2 inhibitors

Abstract

Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-aided drug design paradigms. The free energy perturbation methodology is the most accurate means of estimating relative binding affinities between two inhibitors. However, due to its complexity and computation-intensive nature, practical applications are restricted to analysis of structurally-related inhibitors. Accordingly, there is a need for methods that enable rapid assessment of a large number of structurally-unrelated molecules in a suitably accurate manner. In this article, the free energy perturbation method is compared with molecular mechanics methods to assess the advantages of each in the estimation of relative binding affinities of COX-2 inhibitors. Qualitative predictions of relative binding free energies of COX-2 inhibitors using molecular mechanics methods are discussed and compared with the corresponding free energy perturbation results. The results indicate that the molecular mechanics based methods are useful in the qualitative assessment, while the free energy methods are useful in the quantitative assessment of relative binding affinities of enzyme inhibitors.