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Automated Assessment of Binding Affinity via Alchemical Free Energy Calculations

submitted on 05.02.2020 and posted on 07.02.2020 by Maximilian Kuhn, Stuart Firth-Clark, Paolo Tosco, Antonia S. J. S. Mey, Mark Mackey, Julien Michel
Free energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace and OpenMM and uses the AMBER14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall’s τ was 0.53 ± 0.05 which is broadly comparable to or better than previously reported results using other methods.


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United Kingdom

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Declaration of Conflict of Interest

The authors declare the following competing financial interest(s): M. K., S. F.-C., P. T. and M. M. are Cresset employees. Cresset commercially distributes the Flare software used in this work.


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