Fragment based drug discovery is a powerful technique for finding lead compounds for medicinal chemistry. Crystallographic fragment screening is particularly useful because it informs one not just about whether a fragment binds, but has the advantage of providing information on how it binds. This information allows for rational elaboration and merging of fragments.

However, this comes with a unique challenge: the confidence in the experimental readout, if and how a fragment binds, is tied to the quality of the crystallographic model that can be built. This intimately links crystallographic fragment screening to the general statistical idea of a “model”, and the statistical ideas of goodness of fit and overfitting.

Continue reading →