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Impact of domain knowledge on blinded predictions of binding energies by alchemical free energy calculations

Antonia S J S Mey, Jordi Juárez Jiménez, Julien Michel
doi: https://doi.org/10.1101/150474
Antonia S J S Mey
EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom, E-mail: Tel.: +44 (0)131 650 4797
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  • For correspondence: mail@julienmichel.net
Jordi Juárez Jiménez
EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom, E-mail: Tel.: +44 (0)131 650 4797
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  • For correspondence: mail@julienmichel.net
Julien Michel
EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom, E-mail: Tel.: +44 (0)131 650 4797
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  • For correspondence: mail@julienmichel.net
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Abstract

The drug design data resource (D3R) consortium organises blinded challenges to address the latest advances in computational methods for ligand pose prediction, affinity ranking, and free energy calculations. Within the context of the second D3R Grand Challenge several blinded binding free energies predictions were made for two congeneric series of FXR inhibitors with a semi-automated alchemical free energy calculations workflow featuring the FESetup and SOMD tools. Reasonable performance was observed in retrospective analyses of literature datasets. Nevertheless blinded predictions on the full D3R datasets were poor due to difficulties encountered with the ranking of compounds that vary in their net-charge. Performance increased for predictions that were restricted to subsets of compounds carrying the same net-charge. Disclosure of X-ray crystallography derived binding modes maintained or improved the correlation with experiment in a subsequent rounds of predictions. The best performing protocols on D3R set1 and set2 were comparable or superior to predictions made on the basis of analysis of literature SARs only, and comparable or slightly inferior, to the best submissions from other groups.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted October 10, 2017.
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Impact of domain knowledge on blinded predictions of binding energies by alchemical free energy calculations
Antonia S J S Mey, Jordi Juárez Jiménez, Julien Michel
bioRxiv 150474; doi: https://doi.org/10.1101/150474
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Impact of domain knowledge on blinded predictions of binding energies by alchemical free energy calculations
Antonia S J S Mey, Jordi Juárez Jiménez, Julien Michel
bioRxiv 150474; doi: https://doi.org/10.1101/150474

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