Multiple structures for virtual ligand screening: defining binding site properties-based criteria to optimize the selection of the query.

Structure based virtual ligand screening (SBVLS) methods are widely used in drug discovery programs. When several structures of the target are available, protocols based either on single structure docking or on ensemble docking can be used. The performance of the methods depends on the structure(s) used as a reference, whose choice requires retrospective enrichment studies on benchmarking databases which consume additional resources. In the present study, we have identified several trends in the properties of the binding sites of the structures that led to the optimal performance in retrospective SBVLS tests whatever the docking program used (Surflex-dock or ICM). By assessing their hydrophobicity and comparing their volume and opening, we show that the selection of optimal structures should be possible with no requirement of prior retrospective enrichment studies. If the mean binding site volume is lower than 350 A(3), the structure with the smaller volume should be preferred. In the other cases, the structure with the largest binding site should be preferred. These optimal structures may be either selected for a single structure docking strategy or an ensemble docking strategy. When constructing an ensemble, the opening of the site might be an interesting criterion additionaly to its volume as the most closed structures should not be preferred in the large systems. These "binding site properties-based" guidelines could be helpful to optimize future prospective drug discovery protocols when several structures of the target are available.