Evolution of Alchemical Free Energy Methods in Drug Discovery
Lin Frank Song, Kenneth M. Merz
Abstract
The goal of the present manuscript is to succinctly trace the key technological steps in the evolution of alchemical free energy methods (AFEMs) from a purely theoretical construct to a method that is now widely used in the biotechnological and pharmaceutical industries. More specifically, we focus on relative binding free energy (RBFE) computations which are more routinely applied in computer aided drug design (CADD) campaigns rather than the more computationally intensive absolute binding free energy (ABFE) computations. We have not been exhaustive in the development of our timeline but rather try to weave a story about how theoretical ideas were ultimately converted into contemporary free energy capabilities. Necessarily this story-telling approach limits us from citing all work on AFEMs, and we apologize for this shortcoming. However, for those interested in a broad delineation of all the work done in this area they are directed to the many excellent reviews that are extant.