[20] Use of molecular dynamics and free energy perturbation calculations in anti-human immunodeficiency virus drug design

Abstract

Publisher Summary The chapter describes use of molecular dynamics and free energy perturbation calculation in anti-human immunodeficiency virus(HIV) drug design. Free energy perturbation and related methods have been applied successfully to the calculation of relative binding constants of a number of HIV protease inhibitors, albeit on very small changes. Future studies are likely to involve other HIV targets, such as the reverse transcriptase and gpl20 binding to CD4, when more structural information becomes available. These calculations require a large investment of effort and of computer time. New methods have been developed to increase sampling, to estimate free energy derivatives as a function of parameters, and to break down free energy differences into specific components. These methods will increase the ability of molecular dynamics and free energy calculations to predict new and improved inhibitors. Several modifications to HIV protease and other inhibitors have already been proposed, and experimental testing of these predictions is awaited.