Structure-based drug design approaches for predicting binding affinities of HIV1 protease inhibitors.

Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-assisted drug design (CADD) paradigms. The free energy perturbation (FEP) 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 large number of structurally-unrelated molecules in a suitably accurate manner. In this review, the FEP method is compared with regression-based methods that employ multivariate models to assess the advantages of each in the estimation of relative binding affinities of inhibitors to an enzyme. Semiquantitative predictions of relative binding free energies of human immunodeficiency virus 1 (HIV1) protease inhibitors are also presented and compared with the corresponding FEP results. The results indicate that the regression-based methods and the FEP method are useful in the semi-quantitative and quantitative assessment of relative binding affinities of enzyme inhibitors, respectively, prior to synthesis.