Over the years, fragment-based drug discovery (FBDD) has become a successful alternative to more traditional drug discovery methods such as high-throughput screening. Despite this success, FBDD remains a challenging task due to the relatively weak binding, and mobile nature of fragments. Whilst approaches such as high-throughput crystallography are now routinely used to determine fragment binding poses, reliable means of quantifying affinities, which often lie in the milli to micromolar range, are not readily available for many systems of interest. Computational methods, especially alchemical free energy calculations, are ideally suited to alleviate this issue, offering low-cost orthogonal means of estimating affinities in fragment optimization campaigns. Here we explore the use of Absolute Binding Free Energy (ABFE) calculations as part of the fragment optimization process. Retrospectively calculating free energies for 59 ligands across four FBDD campaigns, we demonstrate that ABFEs can readily rank fragment binders, with a Spearman r of 0.89, and average RMSEs around 2 kcal/mol. We show that specific synthetic decisions can be supported by ABFE results, although this is often limited by large uncertainties in the estimates. We also compare results against those obtained using other methods, including cheaper endpoint free energy estimates obtained via Nwat-MM/GBSA. Finally we discuss the various challenges and lessons learned encountered in applying ABFE calculations to explore fragment binding.

Using absolute binding free energy calculations to guide fragment optimization

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ACS Fall 2022

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