The maximal and current accuracy of rigorous protein-ligand binding free energy calculations.

ABSTRACT: Computational techniques can speed up the identification of hits and accelerate the development of candidate molecules for drug discovery. Among techniques for predicting relative binding affinities, the most consistently accurate is free energy perturbation (FEP), a class of rigorous physics-based methods. However, uncertainty remains about how accurate FEP is and can ever be. Here, we present what we believe to be the largest publicly available dataset of proteins and congeneric series of small molecules, and assess the accuracy of the leading FEP workflow. To ascertain the limit of achievable accuracy, we also survey the reproducibility of experimental relative affinity measurements. We find a wide variability in experimental accuracy and a correspondence between binding and functional

SUBMITTER: Ross GA 

PROVIDER: S-EPMC10576784 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature