Efficient virtual screening using multiple protein conformations described as negative images of the ligand-binding...

The protein structure-based virtual screening is typically accomplished using a molecular docking procedure. However, docking is a fairly slow process that is limited by the available scoring functions that cannot reliably distinguish between active and inactive ligands. In contrast, the ligand-based screening methods that are based on shape similarity identify the active ligands with high accuracy. Here, we show that the usage of negative images of the ligand-binding site, together with shape comparison tools, which are typically used in ligand-based virtual screening, improve the discrimination of active molecules from inactives. In contrast to ligand-based shape comparison, the negative image of the binding site allows identification of compounds whose shape complements the shape of the ligand-binding cavity as closely as possible. Furthermore, the use of several target protein conformations allows the identification of active ligands whose shape is not optimal for crystallized protein conformation. Accordingly, the presented virtual screening method improves the identification of novel lead molecules by concentrating on the optimally shaped molecules for the flexible ligand binding site.