Abstract

Rational, computer-aided design of small molecules with desirable pharmacological properties is needed to reduce the costs and increase the success rate of the drug development process. Free energy methods, in combination with molecular dynamics or Monte Carlo sampling, are particularly attractive because, in principle, they provide a rigorous means to compute the free energy of binding of a potential drug molecule to its receptor.

In this talk, I will review the use of free energy perturbation theory to describe the thermodynamics of drug-receptor binding. I will present some of the pitfalls of the methods, including incomplete sampling of conformational space and inaccuracy in the underlying molecular mechanics force field. Finally, I will describe how we can improve the reliability of free energy methods through enhanced sampling methods and improve their accuracy by parameterising the force field using the ONETEP large-scale quantum mechanics software. These improvements will be illustrated through application to the study of small molecule inhibitors of HIV reverse transcriptase and p38 kinase.