![DCC vs CDC](https://upload.wikimedia.org/wikipedia/commons/d/d0/DCC_vs_CDC.png)
Dynamic combinatorial chemistry (DCC); also known as constitutional dynamic chemistry (CDC) is a method to the generation of new molecules formed by
reversible reaction
A reversible reaction is a reaction in which the conversion of reactants to products and the conversion of products to reactants occur simultaneously.
: \mathit aA + \mathit bB \mathit cC + \mathit dD
A and B can react to form C and D or, in the ...
of simple building blocks under
thermodynamic control
Thermodynamic reaction control or kinetic reaction control in a chemical reaction can decide the composition in a reaction product mixture when competing pathways lead to different products and the reaction conditions influence the selectivity or ...
.
[Schaufelberger, F.; Timmer, B. J. J.; Ramström, O. Principles of Dynamic Covalent Chemistry. In ''Dynamic Covalent Chemistry: Principles, Reactions, and Applications''; Zhang, W.; Jin, Y., Eds.; John Wiley & Sons: Chichester, 2018; Chapter 1, pp 1–30.] The library of these reversibly interconverting building blocks is called a dynamic combinatorial library (DCL).
[Komáromy, D.; Nowak, P.; Otto, S. Dynamic Combinatorial Libraries. In ''Dynamic Covalent Chemistry: Principles, Reactions, and Applications''; Zhang, W.; Jin, Y., Eds.; John Wiley & Sons: Chichester, 2018; Chapter 2, pp 31–119.][Lehn, J.-M.; Ramström, O. Generation and screening of a dynamic combinatorial library. PCT. Int. Appl. WO 20010164605, 2001.] All constituents in a DCL are in
equilibrium, and their distribution is determined by their
thermodynamic stability
In chemistry, chemical stability is the thermodynamic stability of a chemical system.
Thermodynamic stability occurs when a system is in its lowest energy state, or in chemical equilibrium with its environment. This may be a dynamic equilibriu ...
within the DCL. The interconversion of these building blocks may involve
covalent
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
or
non-covalent
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The ...
interactions. When a DCL is exposed to an external influence (such as
proteins or
nucleic acids
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
), the equilibrium shifts and those components that interact with the external influence are
stabilised and
amplified, allowing more of the active compound to be formed.
History
By modern definition, dynamic combinatorial chemistry is generally considered to be a method of facilitating the generation of new chemical species by the reversible linkage of simple building blocks, under thermodynamic control.
This principle is known to select the most thermodynamically stable product from an equilibrating mixture of a number of components, a concept commonly utilised in synthetic chemistry to direct the control of reaction selectivity. Although this approach was arguably utilised in the work of Fischer and Werner as early as the 19th century, their respective studies of carbohydrate and coordination chemistry were restricted to rudimentary speculation, requiring the rationale of modern thermodynamics. It was not until supramolecular chemistry revealed early concepts of molecular recognition, complementarity and self-organisation that chemists could begin to employ strategies for the rational design and synthesis of macromolecular targets. The concept of template synthesis was further developed and rationalised through the pioneering work of Busch in the 1960s, which clearly defined the role of a metal ion template in stabilising the desired ‘thermodynamic’ product, allowing for its isolation from the complex equilibrating mixture. Although the work of Busch helped to establish the template method as a powerful synthetic route to stable macrocyclic structures, this approach remained exclusively within the domain of inorganic chemistry until the early 1990s, when Sanders et al. first proposed the concept of dynamic combinatorial chemistry.
Their work combined thermodynamic templation in tandem with combinatorial chemistry, to generate an ensemble complex porphyrin and imine macrocycles using a modest selection of simple building blocks.
Sanders then developed this early manifestation of dynamic combinatorial chemistry as a strategy for organic synthesis; the first example being the thermodynamically-controlled macrolactonisation of oligocholates to assemble cyclic steroid-derived macrocycles capable of interconversion via component exchange. Early work by Sanders et al. employed transesterification to generate dynamic combinatorial libraries. In retrospect, it was unfortunate that esters were selected for mediating component exchange, as transesterification processes are inherently slow and require vigorous anhydrous conditions.
However, their subsequent investigations identified that both the disulfide and hydrazone covalent bonds exhibit effective component exchange processes and so present a reliable means of generating dynamic combinatorial libraries capable of thermodynamic templation. This chemistry now forms the basis of much research in the developing field of dynamic covalent chemistry, and has in recent years emerged as a powerful tool for the discovery of molecular receptors.
Protein-directed
One of the key developments within the field of DCC is the use of
proteins (or other
biological macromolecules, such as
nucleic acids
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
) to influence the evolution and generation of components within a DCL.
[Greaney, M. F.; Bhat, V. T. Protein-directed dynamic combinatorial chemistry. In ''Dynamic combinatorial chemistry: in drug discovery, bioinorganic chemistry, and materials sciences''; Miller, B. L., Ed.; John Wiley & Sons: New Jersey, 2010; Chapter 2, pp 43–82.] Protein-directed DCC provides a way to generate, identify and rank novel
protein ligands, and therefore have huge potential in the areas of
enzyme inhibition
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
and
drug discovery.
[Hochgürtel, M.; Lehn, J.-M. Dynamic combinatorial diversity in drug discovery. In ''Fragment-based approaches in drug discovery''; Jahnke, W., Erlanson, D. A., Ed.; Wiley-VCH: Weinheim, 2006; Chapter 16, pp 341–364.]
Reversible covalent reactions
![Types of DCC reactions](https://upload.wikimedia.org/wikipedia/commons/e/e8/Types_of_DCC_reactions.PNG)
The development of protein-directed DCC has not been straightforward because the reversible reactions employed must occur in
aqueous solution at biological
pH and
temperature
Temperature is a physical quantity that expresses quantitatively the perceptions of hotness and coldness. Temperature is measurement, measured with a thermometer.
Thermometers are calibrated in various Conversion of units of temperature, temp ...
, and the components of the DCL must be compatible with
proteins.
Several reversible reactions have been proposed and/or applied in protein-directed DCC. These included boronate ester formation,
diselenides-disulfides exchange,
disulphide formation,
hemithiolacetal formation,
hydrazone formation,
imine formation
and thiol-enone exchange.
Pre-equilibrated DCL
For reversible reactions that do not occur in
aqueous buffers, the pre-equilibrated DCC approach can be used. The DCL was initially generated (or pre-equilibrated) in
organic solvent
A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
, and then
diluted into
aqueous buffer containing the
protein target for selection.
Organic based reversible reactions, including
Diels-Alder and
alkene cross metathesis reactions,
have been proposed or applied to protein-directed DCC using this method.
Reversible non-covalent reactions
Reversible
non-covalent
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The ...
reactions, such as
metal
A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typicall ...
-
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
coordination,
has also been applied in protein-directed DCC. This strategy is useful for the investigation of the optimal ligand
stereochemistry to the
binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
of the target
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
.
Enzyme-catalysed reversible reactions
Enzyme-catalysed reversible reactions, such as
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
-catalysed
amide bond formation/hydrolysis reactions and the
aldolase
Fructose-bisphosphate aldolase (), often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phospha ...
-catalysed
aldol reaction
The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.
Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two c ...
s,
have also been applied to protein-directed DCC.
Analytical methods
Protein-directed DCC system must be amenable to efficient
screening
Screening may refer to:
* Screening cultures, a type a medical test that is done to find an infection
* Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees)
* Screening (environmental), a ...
.
Several analytical techniques have been applied to the analysis of protein-directed DCL. These include
HPLC,
mass spectrometry,
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fie ...
,
and
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
.
Multi-protein approach
Although most applications of protein-directed DCC to date involved the use of single protein in the DCL, it is possible to identify protein ligands by using multiple proteins simultaneously, as long as a suitable analytical technique is available to detect the protein species that interact with the DCL components.
This approach may be used to identify specific inhibitors or broad-spectrum enzyme inhibitors.
Other applications
DCC is useful in identifying molecules with unusual binding properties, and provides synthetic routes to complex molecules that aren't easily accessible by other means. These include
smart material
Smart materials, also called intelligent or responsive materials, are designed materials that have one or more properties that can be significantly changed in a controlled fashion by external stimuli, such as stress, moisture, electric or magnetic ...
s,
foldamers
In chemistry, a foldamer is a discrete chain molecule ( oligomer) that folds into a conformationally ordered state in solution. They are artificial molecules that mimic the ability of proteins, nucleic acids, and polysaccharides to fold i ...
,
self-assembling molecules with interlocking architectures and new
soft materials.
The application of DCC to detect
volatile bioactive compounds, ''i.e.'' the amplification and sensing of
scent
An odor (American English) or odour (Commonwealth English; see spelling differences) is caused by one or more volatilized chemical compounds that are generally found in low concentrations that humans and animals can perceive via their sense ...
, was proposed in a concept paper.
Recently, DCC was also used to study the
abiotic origins of life.
See also
*
Combinatorial biology
*
Combinatorial chemistry Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individua ...
*
Drug discovery
*
Fragment-based lead discovery
Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. Fragments are small organic molecules which are small in size and low in mol ...
*
High-throughput screening
High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling ...
References
External links
University of North Carolina at Chapel Hill: Center for Dynamic Combinatorial Chemistry
{{DEFAULTSORT:Dynamic Combinatorial Chemistry
Cheminformatics
Drug discovery
Materials science
Combinatorial chemistry