Prediction of the binding affinity of compounds with diverse scaffolds by MP-CAFEE

Abstract Accurate methods to predict the binding affinities of compounds for target molecules are powerful tools in structure-based drug design (SBDD). A recently developed method called massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) successfully predicted the binding affinities of compounds with relatively similar scaffolds. We investigate the applicability of MP-CAFEE for predicting the affinity of compounds having more diverse scaffolds for the target p38α, a mitogen-activated protein kinase. The calculated and experimental binding affinities correlate well, showing that MP-CAFEE can accurately rank the compounds with diverse scaffolds. We propose a method to determine the optimal number of sampling runs with respect to a predefined level of accuracy, which is established according to the stage in the SBDD process being considered. The optimal number of sampling runs for two key stages—lead identification and lead optimization—is estimated to be five and eight or more, respectively, in our model system using Cochrans sample size formula.