X-ray crystallography: assessment and validation of protein--small molecule complexes for drug discovery

Introduction: Crystallography is the key initial component for structure- and fragment-based drug design and can often generate leads that can be developed into high potency drugs. Therefore, huge sums of money are committed based on the outcome of crystallography experiments and their interpretation. Areas covered: This review discusses how to evaluate the correctness of an X-ray structure, focusing on the validation of small molecule--protein complexes. Various types of inaccuracies found within the Protein Data Bank (PDB) are identified and the ramifications of these errors discussed. The reader will gain an understanding of the key parameters that need to be inspected before a structure can be used in drug discovery efforts, as well as an appreciation of the difficulties of correctly interpreting electron density for small molecules. The reader will also be introduced to methods for validating small molecules within the context of a macromolecular structure. Expert opinion: The quality of structures of small molecules in the PDB varies so widely that the databank should not be considered a reliable repository of structural information about these molecules. This is due to the difficulty in identifying and positioning ligands in medium or low resolution macromolecular crystal structures and the immaturity of the available validation tools. The poor quality of small molecule structures in the PDB hinders the derivation of general principles that govern small molecule-protein interactions.