Free energy perturbation (FEP) is a theoretically rigorous approach for predicting binding free energies. However, practical and scientific issues have limited the use of FEP in pharma. Here, we present recent advances in the application of FEP to real-world projects. We show that accurate and reliable results can be obtained with the incorporation of several new technologies: improved force field (OPLS2.1), enhanced sampling (REST), parallel simulations (GPU), automated setup (Mapper), and error estimates (cycle closure). Results for several hundred ligands show that the FEP approach presented here can reliably obtain high correlations and average errors of approximately 1.0 kcal/mol. 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.

FEP from Schrodinger: A robust solution for accurate free energy predictions in drug discovery

248th National Meeting (2014)

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