PT  - JOURNAL ARTICLE
AU  - Antonia S J S Mey
AU  - Jordi Juárez
AU  - Jiménez
AU  - Julien Michel
TI  - Impact of domain knowledge on blinded predictions of binding energies by alchemical free energy calculations
AID  - 10.1101/150474
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 150474
4099  - http://biorxiv.org/content/early/2017/06/16/150474.short
4100  - http://biorxiv.org/content/early/2017/06/16/150474.full
AB  - 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 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.