Free energy perturbation (FEP) calculations are the gold standard for computationally assessing binding affinities of small molecules to their target proteins. In many cases, calculated binding affinities approach the accuracy of experimental measurements, and data from known molecules facilitate predictions for similar uncharacterized molecules. When used in drug discovery, FEP can expedite the search for more effective drug candidates.

A demonstration run using CDK9 inhibitors narrowed a large set of molecules down to a short list of promising candidates for laboratory testing. FEP calculations identified one previously unknown variant that showed even higher binding affinity than the "hit" molecule from which it was derived.