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X-Ray Crystallography: Assessment and Validation of Protein Small Molecule Complexes for Drug Discovery

Published: Wednesday, August 29, 2012
Last Updated: Wednesday, August 29, 2012
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This review discusses how to evaluate the correctness of an X-ray structure, focusing on the validation of small molecule-protein complexes.

Introduction
Crystallography is the key initial component for structure-based 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
Various types of inaccuracies found within the PDB are identified and the ramifications of these errors are 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
One of the reasons that ligand identification and positioning, within a macromolecular crystal structure, is so difficult is that the quality of small molecules widely varies.

The article is published online in Expert Opinion in Drug Discovery and is free to access.


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