Achieving highly potent binding, while maintaining a host of other ligand properties required for safety and biological efficacy, is a primary objective of small molecule drug discovery.  During the past 15 years, free energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low cost parallel computing.  Such developements have enabled free energy calculations to yield useful comparisons with experiment, and play a role in academic drug discovery efforts. However, it has been challenging to develop free energy calculation protocols that achieve the accuracy, reliability, and throughput that would be needed for such calculations to impact lead optimization in an industrial setting.  We here will report a free energy calculation protocol that appears poised to meet this need, and has provided substantial value in a number of prospective drug discovery collaborations.

Accelerating drug discovery: the role of free energy calculations

249th National Meeting (2015)

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