What+is+Dynamic+Combinatorial+Chemistry+(DCC)

Dynamic Combinatorial Chemistry

Dynamic Combinatorial Chemistry (DCC) is a form of guest-host, supramolecular chemistry that functions on the basic principles of a system in dynamic equilibrium; it is combinatorial chemistry that is under thermodynamic control. In DCC, the system is described by a solution in which a number of constituents are solvated in an environment conducive to rapid, reversible bonds between constituents [1]. As long as the system remains unperturbed, it equilibrates in such a manner that specific products of the reversibly-binding constituents are present in different amounts that allow for the equilibrium, the thermodynamic minima, of the system to be achieved [1].

Once the system equilibrates, the addition of a target molecule to the system will amplify those products that best interact with the target molecule, due to the system’s “desire” to reach its thermodynamic minima. Once the constituents that most favourably interact with the target are bound to it, they can be removed from the equilibrating system, and the equilibrium shifts accordingly. Each of these products is known as a member of a virtual, dynamic library. An individual library member is amplified when it is thermodynamically favourable for it to be a dominant species in the system [1]. It is far more energetically favourable for the system to amplify members that minimize the unfavourable interactions and maximize the favourable ones. DCC systems function on the same principles that allow formation of micelles and binding specificity of antibodies to antigens.

Figure 1 : An example of a dynamic combinatorial library being produced on a nanoparticle. The nanoparticles contain functional groups that participate in reversible covalent bond formation, which leads to formation of dynamic combinatorial library. Once a bio-molecule is introduced into the system, the equilibrium of the system shifts to produce the thermodynamically most favourable product i.e. the nanoparticle that has the highest affinity for the biomolecule.

DCC is being used to investigate new molecular recognition techniques. Molecular recognition, in which a template molecule is introduced into an equilibrium mixture, has been successfully used to identify protein ligands such as ligands for monoclonal antibodies, and active sites for various enzymes such as the active site for carbonic anhydrase [1 ]. Two primary methods by which molecular recognition is achieved are [2] : 1) Receptor assisted casting  2) Substrate assisted molding When using DCC as an interrogative technique on biological molecules, it is important to use both constituents and conditions that are not detrimental to the molecule being interrogated. Among the host of reversible reactions identified in various literature for the use in  dynamic constitutional libraries ( DCLs), the conditions most favourable for use on biological molecules, such as proteins, are [1] : 1) Disulfide exchange  2) Imine Exchange   3) Thioester exchange and exchange of peptide bonds   4) Some hydrazone exchange (limited due to acidic requirements) Dynamic combinatorial methods also have some drawbacks. One of the greatest limitations is due to the fact that a biological receptor molecule requires an aqueous environment to prevent denaturation; as a result, DCL is limited to constituents that are soluble in an aqueous environment [1 ]. A variety of steps have been taken to address this issue, including some steps that were used to better elucidate an inhibitor of the enzyme carbonic anhydrase. During the reasearch, the parent DCL was equilibrated without a template molecule, followed by equilibration of additional DCLs with each missing a single constituent [1] . The DCLs were “frozen”, once equilibrated, and then a deconvolution process was undertaken. In the deconvolution process, enzyme activity assays have been used to determine which library member was the most effective enzyme inhibitor; however, given the complicated method used, similar results could have been achieved through the use of a standard combinatorial library [1]. Return to Combinatorial Chemistry Page Return to FrontPage Go to Proteins Page