Dehydron

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A dehydron is an intramolecular hydrogen bond incompletely shielded from water attack, with a propensity to promote its own dehydration. Dehydrons constitute a special kind of sticky packing defect in proteins that may be exploited to design therapeutic drugs with high target selectivity.[1][2][3][4]

More specifically, dehydrons are partially dehydrated amide-carbonyl hydrogen bonds that result from an incomplete clustering of side-chain nonpolar groups that "wrap" the polar pair within the protein structure. Dehydrons promote the removal of surrounding water through protein associations or ligand binding.[5] This exogenous dehydration enhances the electrostatic interaction between the amide and carbonyl groups by de-shielding their partial charges.[6] Furthermore, the dehydration stabilizes the hydrogen bond by destabilizing the nonbonded state consisting of dehydrated isolated charges. Hence, the name dehydron makes reference to the tendency to promote its dehydration, a process both energetically and thermodynamically favored.[7] Due to their dehydration propensity, dehydrons are markers for protein interactivity,[8] and hence functional indicators, and may serve as drug targets.[9]

Dehydron patterns are not conserved across proteins with common ancestry (paralogs), hence dehydrons constitute structural singularities that may be targeted by drug ligands to control specificity in molecular therapy. This observation heralded a novel approach to molecular targeted therapy, "wrapping technology".[10][11][12]

Besides leading to the wrapping concept in drug design, the evolution of dehydron patterns in proteins with common ancestry has also significant implications for the onset of complexity. This aspect of dehydrons has been reviewed in Nature,[13] BBC News,[14] Scientific American,[15] Chemistry World (Royal Society of Chemistry, UK),[16] and other venues.

Dehydrons were discovered by Ariel Fernandez and coworkers Ridgway Scott, from The University of Chicago and Harold Scheraga, from Cornell University.

Related software

  • Dehydron. A PyMOL plugin to calculate dehydrons and display them onto protein structures.

References

  1. ^ "Review by Philip Ball entitled "Water as an active constituent in Cell Biology", Chemical Reviews (American Chemical Society) vol. 108, pages 74-108, references 268-271". 
  2. ^ "Review by Sarah Crunkhorn on the dehydron concept in Nature Reviews Drug Discovery". 
  3. ^ "Review in Chemistry World (Royal Society of Chemistry) on dehydron-based redesign of anticancer drug imatinib". 
  4. ^ "Transformative Concepts for Drug Design: Target Wrapping", by Ariel Fernandez (ISBN 978-3642117916, Springer-Verlag, Berlin, Heidelberg, 2010, pages 1-15).
  5. ^ "Editor-commended review on dehydron-based drug redesign by Prof. George Demetri in The Journal of Clinical Investigation". 
  6. ^ "Review on the physics of dehydrons by Ariel Fernandez and Alejandro Crespo in Chemical Society Reviews". 
  7. ^ "Review on the physics of dehydrons by Ariel Fernandez and Alejandro Crespo in Chemical Society Reviews". 
  8. ^ "Review on dehydrons in human evolution for Project Syndicate". 
  9. ^ "Review on the physics of dehydrons by Ariel Fernandez and Alejandro Crespo in Chemical Society Reviews". 
  10. ^ Crunkhorn, S.: Anticancer Drugs: Redesigning kinase inhibitors. Nature Reviews Drug Discovery 7, 120-121 (2008)
  11. ^ Demetri, G: Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. Journal of Clinical Investigation 117, 3650-3653 (2007)
  12. ^ "Transformative Concepts for Drug Design: Target Wrapping", by Ariel Fernandez (ISBN 978-3642117916, Springer-Verlag, Berlin, Heidelberg, 2010).
  13. ^ "Review on evolutionary aspects of dehydron patterns in Nature". 
  14. ^ "Review on evolutionary aspects of dehydrons in BBC News". 
  15. ^ "Review of dehydrons in evolution in Scientific American". 
  16. ^ "Review on evolutionary aspects of dehydrons in Chemistry World (The Royal Society of Chemistry, UK)". 

Primary papers

  • Fernandez, A. and Scott, L. R. Phys. Rev. Lett. 91, 08102 (2003)
  • Fernandez, A., Rogale, K., Scott, R. and Scheraga, H. A. Proc. Natl. Acad. Sci. USA 101, 11640-11645 (2004)
  • Fernandez, A. Nature Biotechnology 22, 1081-1085 (2004)
  • Fernandez A, et al. Cancer Research 67, 4028-4033 (2007) Priority Report
  • Fernandez A and Lynch, M. Nature 474, 502-505 (2011)