Estimation of Absolute Binding Free Energies for Drugs That Bind Multiple Proteins

The Gibbs energy of binding (absolute binding free energy, ABFE) of a drug to proteins in the body determines the drug's affinity to its molecular target and its selectivity. ABFE is challenging to measure, and experimental values are not available for many proteins together with potential drugs and other molecules that bind them. Accurate means of calculating such values are, therefore, highly in demand. Realizing that toxicity and side effects are closely related to off-target binding, here we calculate the ABFE of two drugs, each to multiple proteins, in order to examine whether it is possible to carry out such calculations and achieve the required accuracy. The methods that were used were free energy perturbation with replica exchange molecular dynamics (FEP/REMD) and density functional theory (DFT) with a cluster approach and a simplified model. DFT calculations were supplemented with energy decomposition analysis (EDA). The accuracy of each method is discussed, and suggestions are made for the approach toward better ABFE calculations.