Previously, BLUES has been successfully used to study multiple binding modes of rigid fragments -toluene binding to T4-lysozyme and caffeine binding to metabolizing enzyme Cytochrome P450 1A2. The NCMC protocol used random ligand rotation around the centre of mass of the ligand to sample different binding modes. However, simple rigid-body rotational moves are not sufficient to sample the binding modes of drug-like molecules, which can have conformational degrees of freedom in the binding pocket in addition to rotational and translational ones.