Modern Alchemical Free Energy Methods for Drug Discovery Explained

Abstract

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 technologies. The narrative attempts to answer basic questions about what goes on "under the hood" in free energy simulations and provide general guidelines for how to run simulations and analyze the results. It is the hope that this work will provide a valuable introduction to students and scientists in the field.

Figure 1

Illustration of a thermodynamic cycle for the relative binding free energy (RBFE, ΔΔG_bind) between two ligands (“Ligand 1” and “Ligand 2”). The green arrows represent the absolute binding free energy (ABFE, ΔG_bind) of each ligand (indicated by the superscript), which involves changing the environment from unbound in the aqueous phase to bound in a complex with the protein target. These quantities are experimentally measurable but are challenging to directly compute, as the change in the environment can be considerably complicated. The red arrows represent alchemical transformations where Ligand 1 is mutated into a similar Ligand 2 in the same environment. These transformations are frequently more amenable to practical computations. The yellow circles in the figures indicate the region of each ligand that undergoes the most significant changes in the alchemical transformation and would likely be modeled using a “softcore potential” during the alchemical transformation.