This Perspective provides a contextual explanation of the current state-of-the-art alchemical
free energy methods and their role in drug discovery as well as highlights select emerging …

Computational methods constitute efficient strategies for screening and optimizing potential
drug molecules. A critical factor in this process is the binding affinity between candidate …

Alchemical absolute binding free energy (ABFE) calculations have substantial potential in
drug discovery, but are often prohibitively computationally expensive. To unlock their …

In drug discovery, the in silico prediction of binding affinity is one of the major means to
prioritize compounds for synthesis. Alchemical relative binding free energy (RBFE) …

Alchemical absolute binding free energy calculations are of increasing interest in drug
discovery. These calculations require restraints between the receptor and ligand to restrict …

An alchemical enhanced sampling (ACES) method has recently been introduced to facilitate
importance sampling in free energy simulations. The method achieves enhanced sampling …

The accurate prediction of protein–ligand binding affinities is crucial for drug discovery.
Alchemical free energy calculations have become a popular tool for this purpose. However …

Relative binding free energy (RBFE) calculations have emerged as a powerful tool that
supports ligand optimization in drug discovery. Despite many successes, the use of RBFEs …

Alchemical free energy (AFE) calculations can predict binding affinity changes as a function
of structural modifications and have become powerful tools for lead optimization and drug …

1Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA,
USA, 2Department of Biochemistry and Biophysics, Washington University in St. Louis, St …