Dehydron
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-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
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).
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
incompletely shielded from water attack
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, with a propensity to promote its own dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
. Dehydrons constitute a special kind of packing defect in soluble proteins and were named and characterized by Argentine-American scientist Ariel Fernandez
Ariel Fernandez
Ariel Fernandez is an Argentinian-American physical chemist who held the Karl F. Hasselmann Professorship of Bioengineering at Rice University until 2011. He was born in Bahía Blanca, Argentina in 1957 and is currently involved in technology development at the , where he has been named...
, from Rice University, and his coworkers Ridgway Scott, Stephen Berry and Harold Scheraga.
Dehydrons are partially dehydrated amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
-carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
hydrogen bonds that result from an incomplete clustering of side-chain nonpolar groups that "wrap" the polar
Chemical polarity
In chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
pair within the protein structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
. Dehydrons are sticky
Sticky
Sticky may refer to:* Adhesion* Sticky , resistant to change* Sticky , a book of gay erotic comics* Sticky Fingaz or Sticky, nickname of the US rapper and actor Kirk Jones* Sticky note, a generic term for a Post-it note or competitor...
, since they promote the removal of surrounding water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
through protein associations or ligand binding
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
. The exogenous dehydration enhances the electrostatic interaction
Interaction
Interaction is a kind of action that occurs as two or more objects have an effect upon one another. The idea of a two-way effect is essential in the concept of interaction, as opposed to a one-way causal effect...
between the amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
and carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
groups by de-shielding their partial charges
Charge (physics)
In physics, a charge may refer to one of many different quantities, such as the electric charge in electromagnetism or the color charge in quantum chromodynamics. Charges are associated with conserved quantum numbers.-Formal definition:...
. Furthermore, the dehydration stabilizes the hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
by destabilizing the nonbonded state consisting of dehydrated isolated charges
Charge (physics)
In physics, a charge may refer to one of many different quantities, such as the electric charge in electromagnetism or the color charge in quantum chromodynamics. Charges are associated with conserved quantum numbers.-Formal definition:...
. Hence, the name dehydron makes reference to the tendency to promote its dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, a process both energetically
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
and thermodynamically
Thermodynamics
Thermodynamics is a physical science that studies the effects on material bodies, and on radiation in regions of space, of transfer of heat and of work done on or by the bodies or radiation...
favored. Due to their dehydration propensity, dehydrons are markers for protein interactivity
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, hence functional indicators, and may serve as drug targets
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
.
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).