Free Energy Perturbation (FEP) calculations allow for prediction of relative binding affinity changes within a congeneric ligand series. In these calculations a molecule is gradually converted into a structurally closely related ligand via a non-physical (‘alchemical’) pathway. By assessing the free energy difference (ΔΔG) between the end states of such transformations, accuracies of about 1 kcal/mol compared to experimental values can be achieved for large datasets.<br/><br/>However, routine application of FEP calculations is still hampered by a lack of automation. Though several open-source applications strive to make FEP more accessible (e.g., the Sire molecular simulation package), installing and using these relatively complex tools requires expertise. To remove this obstacle, a fully automated workflow for performing FEP calculations has been implemented in the recently released version 3.0 of Cresset’s drug design software Flare.<br/><br/>The workflow was validated using different datasets, including the FEP+ dataset as a benchmark. Results obtained with this method were broadly comparable to published reports, considering the overall reduced simulation time. Since the ideal simulation parameters for a given set of ligands and their target protein cannot easily be estimated in advance, power users have full control over on simulation parameters via Flare’s GUI and Python API.

Automated assessment of binding affinity via free energy perturbation

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.