Consequently, the approximate binding free energies may be higher (i.e., weaker binding) than if flexibility were allowed for either the protein, the ligand, or both. We chose rigid body docking to avoid the substantial inaccuracies often introduced by ligand or protein flexibility at this stage. Nonetheless, refining these four sets of 300 combined hit lists using higher-quality methods-which allow for accurate geometry relaxation in both the ligand and protein and capturing more precise intermolecular interactions-would be worthwhile. We are currently developing such methods, incorporating our new QM/MM scheme, and it is also possible to refine these hit lists with relatively accurate MD-based approaches.