title: The future of crystallography in drug discovery.
abstract: BACKGROUND
  X-ray crystallography plays an important role in structure-based drug design (SBDD), and accurate analysis of crystal structures of target macromolecules and macromolecule-ligand complexes is critical at all stages. However, whereas there has been significant progress in improving methods of structural biology, particularly in X-ray crystallography, corresponding progress in the development of computational methods (such as in silico high-throughput screening) is still on the horizon. Crystal structures can be overinterpreted and thus bias hypotheses and follow-up experiments. As in any experimental science, the models of macromolecular structures derived from X-ray diffraction data have their limitations, which need to be critically evaluated and well understood for structure-based drug discovery.
  
  
  METHODS
  This review describes how the validity, accuracy and precision of a protein or nucleic acid structure determined by X-ray crystallography can be evaluated from three different perspectives: i) the nature of the diffraction experiment; ii) the interpretation of an electron density map; and iii) the interpretation of the structural model in terms of function and mechanism. The strategies to optimally exploit a macromolecular structure are also discussed in the context of 'Big Data' analysis, biochemical experimental design and structure-based drug discovery.
  
  
  CONCLUSIONS
  Although X-ray crystallography is one of the most detailed 'microscopes' available today for examining macromolecular structures, the authors would like to re-emphasize that such structures are only simplified models of the target macromolecules. The authors also wish to reinforce the idea that a structure should not be thought of as a set of precise coordinates but rather as a framework for generating hypotheses to be explored. Numerous biochemical and biophysical experiments, including new diffraction experiments, can and should be performed to verify or falsify these hypotheses. X-ray crystallography will find its future application in drug discovery by the development of specific tools that would allow realistic interpretation of the outcome coordinates and/or support testing of these hypotheses.
authors.affiliation: University of Virginia, Department of Molecular Physiology and Biological Physics , 1340 Jefferson Park Avenue, Charlottesville, VA 22908 , USA.
authors.forename: Heping
authors.initials: H
authors.lastname: Zheng
authors.forename: Jing
authors.initials: J
authors.lastname: Hou
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Zimmerman
authors.forename: Alexander
authors.initials: A
authors.lastname: Wlodawer
authors.forename: Wladek
authors.initials: W
authors.lastname: Minor
mesh_terms: D018360:Crystallography, X-Ray; D055808:Drug Discovery; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins