Dehydron

From Wikipedia, the free encyclopedia

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 packing defect in soluble proteins and were named and characterized by Argentine-born American scientist Ariel Fernandez, from Rice University, and his coworkers Ridgway Scott, Stephen Berry and Harold Scheraga.

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 are sticky, since they promote the removal of surrounding water through protein associations and/or ligand binding. This further dehydration enhances the electrostatic interaction between the amide and carbonyl groups by de-shielding their partial charges. Furthermore, the dehydration stabilizes the hydrogen bond by destabilizing the nonbonded state that consists of dehydrated isolated charges. Hence, the name dehydron makes reference to the tendency to promote its dehydration, a process both energetically and thermodynamically favored. Thus, dehydrons are markers for protein interactivity, and hence functional indicators, and may possibly serve as drug targets.

Dehydron patterns are not conserved across proteins with common ancestry (paralogs), hence dehydrons constitute structural singularities that have been targeted by drug ligands to achieve higher specificity and ultimately, to control side effects. This observation prompted researchers to introduce the design concept of "drug as dehydron wrapper", and heralded the advent of a novel approach to drug development, the so-called "wrapping technology".

The design concept of dehydron as a selectivity-promoting feature to reduce side effects in drugs has been recently highlighted:

  • Crunkhorn, S.: Anticancer Drugs: Redesigning kinase inhibitors. Nature Reviews Drug Discovery 7, 120-121 (2008)
  • Demetri, G: Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. Journal of Clinical Investigation 117, 3650-3653 (2007))

[edit] References:

  • Fernandez, A. and Scott, L. R. Phys. Rev. Lett. 91, 08102 (2003).
  • Fernandez, A. and Berry, R. S. Proc. Natl. Acad. Sci. USA 101, 13460-13465 (2004).
  • Fernandez, A. Nature Biotechnology 22, 1081-1085 (2004).
  • Fernandez A, et al. Cancer Research 67, 4028-4033 (2007) Priority Report.
  • Chen, J. P., Zhang, X. and Fernandez, A. Bioinformatics 23, 563-572 (2007)
  • Crespo, A. and Fernandez, A. Drug Discovery Today 12, 917-923 (2007)
  • Fernandez, A. et al. Journal of Clinical Investigation 117, 4044-4054 (2007)