David Wright, Benjamin Hall, Owain Kenway, Shantenu Jha and Peter Coveney have published an article in the Journal of Chemical Theory and Computation on the use of molecular simulations to evaluate the binding of clinically relevant inhibitors to HIV-1 protease. You can find the paper here.
The use of molecular simulation to estimate the strength of macromolecular binding free energies is becoming increasingly widespread, with goals ranging from lead optimisation and enrichment in drug discovery to personalising or stratifying treatment regimes. In order to realise the potential of such approaches to predict new results, not merely to explain previous experimental findings, it is necessary that the methods used are reliable and accurate.
The authors have used ensemble molecular dynamics simulations to validate and verify two of the most widely used free energy techniques, molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA). Furthermore the authors developed a novel variation on these methods which better accounts for the contribution of solute entropy changes to binding.
This study was made possible by the use of supercomputers on both the US XSEDE and EU PRACE networks alongside UK resources such as the Emerald GPU cluster and UCL Legion service. Using the authors' new methodology they managed to correctly rank and differentiate 7 FDA approved HIV-1 protease inhibitors and provide a thorough assessment of what is required to produce converged and hence reliable free energies for protein-ligand binding more generally.
The authors believe that this work should set a precedent for future work leading to increased accuracy, repeatability and reproducibility of binding affinities between drugs, proteins and other moieties.