X-ray crystallography over the past decade for novel drug discovery - where are we heading next?

Expert Opin Drug Discov. 2015;10(9):975-89. doi: 10.1517/17460441.2015.1061991. Epub 2015 Jul 15.


Introduction: Macromolecular X-ray crystallography has been the primary methodology for determining the three-dimensional structures of proteins, nucleic acids and viruses. Structural information has paved the way for structure-guided drug discovery and laid the foundations for structural bioinformatics. However, X-ray crystallography still has a few fundamental limitations, some of which may be overcome and complemented using emerging methods and technologies in other areas of structural biology.

Areas covered: This review describes how structural knowledge gained from X-ray crystallography has been used to advance other biophysical methods for structure determination (and vice versa). This article also covers current practices for integrating data generated by other biochemical and biophysical methods with those obtained from X-ray crystallography. Finally, the authors articulate their vision about how a combination of structural and biochemical/biophysical methods may improve our understanding of biological processes and interactions.

Expert opinion: X-ray crystallography has been, and will continue to serve as, the central source of experimental structural biology data used in the discovery of new drugs. However, other structural biology techniques are useful not only to overcome the major limitation of X-ray crystallography, but also to provide complementary structural data that is useful in drug discovery. The use of recent advancements in biochemical, spectroscopy and bioinformatics methods may revolutionize drug discovery, albeit only when these data are combined and analyzed with effective data management systems. Accurate and complete data management is crucial for developing experimental procedures that are robust and reproducible.

Keywords: data management; hybrid methods; protein crystallography; reproducibility; structural data interpretation; target-based drug discovery.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Computational Biology
  • Crystallography, X-Ray / methods*
  • Drug Design*
  • Drug Discovery / trends*
  • Humans
  • Pharmaceutical Preparations / chemistry
  • Reproducibility of Results


  • Pharmaceutical Preparations