Schrödinger FEP+ High-performance free energy calculations for drug discovery The Advantages of Free Energy Perturbation Calculations Achieving highly potent binding, while maintaining a host of other ligand properties required for safety and biological efficacy, is a primary objective of small molecule drug discovery. Historically, it has been challenging for free energy calculations to achieve the accuracy, reliability, ease of use, and throughput that are required to impact lead optimization in an industrial setting. Thanks to recent advances in force fields and sampling algorithms, coupled with the availability of low-cost parallel computing, free energy calculations can now yield meaningful comparisons with experimental binding affinities. The confluence of these advances is allowing in silico simulations to contribute to real-life drug discovery efforts by providing better synthesis decisions during lead optimization. Features Publications FEP+ Compatible Systems State-of-the-art Force Field: The OPLS3e force field incorporates refined van der Waals parameters and partial charges, as well as >10,000 additional torsional parameters optimized for drug-like molecules. In addition, the OPLS3e force field contains improved parameters for proteins and nucleic acids, expanded small molecule torsional coverage, and off-atom charge sites to represent halogen bonding and aryl nitrogen lone pair interactions. These improvements have enabled the OPLS3e force field to achieve high accuracy in the modeling of protein dynamics, small molecule solvation and small conformational energetics, and protein-ligand binding. Intuitive GUI: The FEP+ GUI allows users to easily set up the desired perturbations without requiring expert knowledge of the complex calculations that are automated behind the scenes. Powerful analysis tools also make it possible to visualize and examine the computed results. Enhanced Sampling: Incorporation of the REST (replica exchange with solute tempering) enhanced sampling methodology enables detailed-balance-preserving simulation of a selected subsystem at a higher effective temperature, thereby focusing sampling efforts to most efficiently traverse the relevant phase space. Error Estimates: The FEP Mapper interface elucidates the network of transformations and facilitates the analysis of the consistency and convergence of the simulation results by identifying sub-calculations that may require attention as well as providing error estimates from individual simulations. GPU-enabled: Optimization of the FEP+ algorithm to take full advantage of the Desmond GPU MD engine enabling 2 to 4 ligands to be scored per day on a relatively inexpensive 4 GPU server. Citations and Acknowledgements Schrödinger Release 2021-4: FEP+, Schrödinger, New York, NY, 2021. ö Abel, R.; Wang, L.; Harder, E.D.; Berne, B.J.; Friesner, R.A., "Advancing Drug Discovery through Enhanced Free Energy Calculations," Acc. Chem. Res., 2017 50 (7), 1625-1632 ö Kuhn, B.; Tichý, M.; Wang, L.; Robinson, S.; Martin, R.E.; Kuglstatter, A.; Benz, J.; Giroud, M., Schirmeister, T.; Abel, R.; Diederich, F.; Hert, J., "Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors," J. Med. Chem., 2017, 60 (6), 2485-2497 ö Yu, H.S.; Deng, Y.; Wu, Y.; Sindhikara, D.; Rask, A.R.; Kimura, T.; Abel, R.; Wang, L., "Accurate and Reliable Prediction of the Binding Affinities of Macrocycles to Their Protein Targets," J. Chem Theory Comput., 2017, 13 (12), 6290-6300 ö Wang, L.; Deng, Y.; Wu, Y.; Kim, B.; LeBard, D.N.; Wandschneider, D.; Beachy, M.; Friesner, R.A; Abel, R., "Accurate Modeling of Scaffold Hopping Transformations in Drug Discovery," J. Chem Theory Comput., 2017, 13 (1), 42-54 ö Harder, E.; Damm, W.; Maple, J.; Wu, C.; Reboul, M.; Xiang, J.Y.; Wang, L.; Lupyan, D.; Dahlgren, M.K.; Knight, J.L.; Kaus, J.W.; Cerutti, D.S.; Krilov, G.; Jorgensen, W.L.; Abel, R.; Friesner, R.A., "OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins," J. Chem. Theory Comput., 2016, 2 (1), 281–296 ö Wang, L.; Wu, Y.; Deng, Y.; Kim, B.; Pierce, L.; Krilov, G.; Lupyan, D.; Robinson, S.; Dahlgren, M.K.; Greenwood, J.; et al., "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. 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