An early requirement of many drug discovery projects is the design or discovery of a small organic molecule that binds a disease-related protein with high affinity; i.e., with strongly negative free energy. Computational methods of estimating protein-small molecule binding free energies may be used to help at this project stage. However, current computational methods are not yet accurate enough to obviate the need for synthesis and testing of hundreds or thousands of small molecules to discover a potent drug candidate. Researchers in academia and industry are therefore working to improve accuracy and thus reduce the time and costs of drug discovery.