Limitations and lessons in the use of X-ray structural information in drug design

The use of X-ray crystal structure models continues to provide a strong stimulus to drug discovery, through the direct visualisation of ligand–receptor interactions. There is sometimes a limited appreciation of the uncertainties introduced during the process of deriving an atomic model from the experimentally observed electron density. Here, some of these uncertainties are highlighted with recent examples from the literature, together with snippets of advice for the medicinal chemist embarking on using X-ray crystal structure information in a drug discovery programme.