RosettaLigandEnsemble: A Small-Molecule Ensemble-Driven Docking Approach

[Image: see text] RosettaLigand is a protein–small-molecule (ligand) docking software capable of predicting binding poses and is used for virtual screening of medium-sized ligand libraries. Structurally similar small molecules are generally found to bind in the same pose to one binding pocket, despite some prominent exceptions. To make use of this information, we have developed RosettaLigandEnsemble (RLE). RLE docks a superimposed ensemble of congeneric ligands simultaneously. The program determines a well-scoring overall pose for this superimposed ensemble before independently optimizing individual protein–small-molecule interfaces. In a cross-docking benchmark of 89 protein–small-molecule co-crystal structures across 20 biological systems, we found that RLE improved sampling efficiency in 62 cases, with an average change of 18%. In addition, RLE generated more consistent docking results within a congeneric series and was capable of rescuing the unsuccessful docking of individual ligands, identifying a nativelike top-scoring model in 10 additional cases. The improvement in RLE is driven by a balance between having a sizable common chemical scaffold and meaningful modifications to distal groups. The new ensemble docking algorithm will work well in conjunction with medicinal chemistry structure–activity relationship (SAR) studies to more accurately recapitulate protein–ligand interfaces. We also tested whether optimizing the rank correlation of RLE-binding scores to SAR data in the refinement step helps the high-resolution positioning of the ligand. However, no significant improvement was observed.