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

The drug design data resource (D3R) consortium organises blinded challenges to address the latest advances in computational methods for ligand pose prediction, anity 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 freeenergy calculations workflow featuring the FESetup and SOMD tools. Reasonable performance was observed in retrospective analyses of literature datasets. Never-theless blinded predictions on the full D3R datasets were poor due to diculties
encountered with the ranking of compounds that vary in their net-charge. Per-formance 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