Protein-ligand docking tends to be very good at generating binding modes that resemble experimental binding modes from X-ray crystallography and other methods (assuming we have a high quality structure…); but it is also very good at generating plausible models for ligands that don’t bind. These so-called “false positives” lead to reduced accuracy in structure-based virtual screening campaigns.
Structure-based methods are not the only way of approaching virtual screening: when all we know is the chemical structure of an active molecule, but nothing about its target (or targets), we can use ligand-based virtual screening methods, which operate on the principle of molecular similarity (Maggiora et al., 2014).
But what if we combine both methods?