Alchemical free energy methods for drug discovery: progress and challenges

Improved rational drug design methods are needed to lower the cost and increase the success rate of drug discovery and development. Alchemical binding free energy calculations, one potential tool for rational design, have progressed rapidly over the past decade, but still fall short of providing robust tools for pharmaceutical engineering. Recent studies, especially on model receptor systems, have clarified many of the challenges that must be overcome for robust predictions of binding affinity to be useful in rational design. In this review, inspired by a recent joint academic/industry meeting organized by the authors, we discuss these challenges and suggest a number of promising approaches for overcoming them.

Research highlights► Improved rational drug design methods are needed to reduce cost of drug discovery. ► Alchemical free energy methods provide physical detail lacking in virtual screening. ► Absolute binding affinities yield insight into challenges for quantitative theory. ► Moving from pure research to engineering requires changes in approach.