The ACS National Meeting this week in San Diego had computers in chemistry as its theme. A number of sessions featured computer-aided drug design, and the paper that garnered a lot of attention in many of these sessions was one I missed from last year. The work, done by the Schrödinger company, presents the application of some improved techniques for performing free energy perturbation (FEP) computations.¹ FEP involves changing a small number of atoms from one type to another and determining the free energy change with this perturbation. Since so much of the system is left unaffected, the idea is that errors in the non-perturbed parts of the system will cancel, allowing for accurate determination of the free energy change due to the perturbation.

This study features a number of new technologies that have enabled much more accurate predictions. First, they have employed a new force field, OPLS2.1, which appears to provide much improved energies. Second, they have improved sampling of configuration space using the Desmond program and replica exchange with solute tempering (REST). Third, these have been implemented on GPUs that results in dramatically improved throughput. And fourth, they developed a workflow to automate the selection of ligands, created by the perturbations with the protein of interest. They examined up to 10 atom perturbations within the initial ligand.

In a validation study of 8 proteins involving 330 ligands, the RMS error in the free energy of binding was about 1 kcal mol^-1. Case studies of different types of perturbations leading to gain or loss of hydrophobic or electrostatic interactions, loss of a binding water and exposure to solvent are detailed. Lastly, in a study of two new proteins, they report a high success in predicting both strong binders and weak binders, with very few false positives.

References

(1) Wang, L.; Wu, Y.; Deng, Y.; Kim, B.; Pierce, L.; Krilov, G.; Lupyan, D.; Robinson, S.; Dahlgren, M. K.; Greenwood, J.; Romero, D. L.; Masse, C.; Knight, J. L.; Steinbrecher, T.; Beuming, T.; Damm, W.; Harder, E.; Sherman, W.; Brewer, M.; Wester, R.; Murcko, M.; Frye, L.; Farid, R.; Lin, T.; Mobley, D. L.; Jorgensen, W. L.; Berne, B. J.; Friesner, R. A.; Abel, R. "Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field," J. Am. Chem. Soc. 2015, 137, 2695-2703, DOI: 10.1021/ja512751q.