Free energy perturbation (FEP)  with explicit solvent molecular dynamics (MD) offers a theoretical precise platform for determining the free energy of binding for molecules to receptors. In the past, the practical application of FEP to pharmaceutically relevant problems has been limited due to requirement of extensive computational resources, complex setup, force field limitations, and expert user decisions. However, modern MD codes, fast GPU technology, and automated workflows have begun to make FEP accessible in a pharmaceutical research setting. Here, we present recent advances in the application of FEP to real-world projects involving solvation and binding free energies. We present our recent application in predicting enthalpy and entropy of hydration and show a high correlation with ITC data. We also apply an advanced FEP workflow that involves several new technologies, such as next generation force fields (OPLS2.1), enhanced sampling (REST), parallel simulations (GPU), automated setup (Mapper), and error estimates (cycle closure) to estimate binding free energies of several hundred ligands and obtained high correlations and low average errors. We demonstrate the value of FEP in prospective drug discovery projects and describe our work to further expand the domain of applicability of the method.

Large-scale application of free energy perturbation (FEP) to affinity optimization in drug discovery

248th National Meeting (2014)

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