Dehydron

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-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 or ligand binding. The exogenous 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 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. Due to their dehydration propensity, dehydrons are markers for protein interactivity, hence functional indicators, and may serve as drug targets.

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. Ultimately, the goal of this design concept is to enhance safety by reducing side effects in a controllable rational manner. This observation prompted researchers to introduce the paradigm of "drug as dehydron wrapper", and heralded the advent of a novel approach to molecular targeted therapy, the so-called "wrapping technology".

The design concept of dehydron as selectivity-promoting feature is highlighted in

• 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))

The wrapping technology in drug design is featured at a fundamental and applied level in the book "Transformative Concepts for Drug Design: Target Wrapping", by Ariel Fernandez (ISBN 978-3642117916, Springer-Verlag, Berlin, Heidelberg, 2010).

References

• 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. 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)
• Fernandez, A. "Transformative Concepts for Drug Design: Target Wrapping" (ISBN 978-3642117916), Springer-Verlag, Berlin, Heidelberg (2010).