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Drug discovery by dynamic combinatorial libraries

Key Points

  • Dynamic combinatorial chemistry is a supramolecular approach that uses a self-assembly process to generate libraries of chemical compounds. Spontaneous assembly of the building blocks through reversible chemical reactions can, in principle, encompass all possible combinations.

  • Addition of a target molecule to a dynamic combinatorial library (DCL) creates a driving force that favours the formation of the best-binding constituent — a self-screening process that can, in principle, greatly accelerate the identification of lead compounds for drug discovery.

  • The generation of DCLs can essentially be accomplished using any type of reversible physical or chemical mechanism, as long as the respective interconverting states can be properly controlled and the final products identified. For drug discovery, it is also important that the reaction mechanism is compatible with biological targets.

  • For a DCL to be efficiently produced, the building blocks need to fulfil several important characteristics. First, they must possess functional groups that can undergo reversible exchange. Second, they must cover as completely as possible the geometrical and functional space of the potential target. Third, these recognition groups need to be organized geometrically for optimal binding to occur.

  • Three approaches to DCL generation and screening have been developed, which have a common first reversible generation step, but differ in the screening/selection phase:

  • Adaptive DCLs: generation of the DCL is done in the presence of the target, resulting in amplification of the best-bound species, so that screening takes place simultaneously in the same compartment.

  • Pre-equilibrated DCLs: generation of the DCL is achieved under reversible conditions, and the identification/screening is done under static conditions. No amplification can take place in this case, but this type of protocol is useful when working with sensitive biological target species that are unavailable in large amounts.

  • Iterative DCLs: Generation of the DCL is achieved in one compartment under appropriate conditions, then in a subsequent step, members of the DCL are allowed to interact with the target species, either in the same reaction chamber or separately. Unbound species are then re-transferred to the reaction chamber, re-scrambled, and again allowed to interact with binding site. After several rounds, the accumulated active species can be analysed.

Abstract

Dynamic combinatorial chemistry is a recently introduced supramolecular approach that uses self-assembly processes to generate libraries of chemical compounds. In contrast to the stepwise methodology of classical combinatorial techniques, dynamic combinatorial chemistry allows for the generation of libraries based on the continuous interconversion between the library constituents. Spontaneous assembly of the building blocks through reversible chemical reactions virtually encompasses all possible combinations, and allows the establishment of adaptive processes owing to the dynamic interchange of the library constituents. Addition of the target ligand or receptor creates a driving force that favours the formation of the best-binding constituent — a self-screening process that is capable, in principle, of accelerating the identification of lead compounds for drug discovery.

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Figure 1: Schematic representation of the concepts behind dynamic combinatorial chemistry and virtual combinatorial libraries.
Figure 2: Essential elements of a dynamic combinatorial library.
Figure 3: Dynamic combinatorial library of circular helicates.
Figure 4: Generation and screening of peptides generated by reversible proteolysis.
Figure 5: Dynamic combinatorial library of imines interacting with carbonic anhydrase.
Figure 6: Dynamic deconvolution of acyl hydrazone libraries of potential inhibitors of acetylcholinesterase.
Figure 7: Dynamic library of disulphide-containing carbohydrate structures.
Figure 8: Library of Zn2+ complexes interacting with duplex DNA.
Figure 9: Receptor library screened against the bacterial cell wall building block d-Ala-d-Ala.

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vancomycin

Glossary

COMBINATORIAL CHEMISTRY

The generation of large collections, or 'libraries', of compounds by synthesizing all possible combinations of a set of smaller chemical structures, or 'building blocks'.

PARALLEL SYNTHESIS

Strategy by which sets of discrete compounds are prepared simultaneously in arrays of physically separate reaction vessels or microcompartments without interchange of intermediates during the assembly process.

RESIN

Synthesis of compounds on the solid surface of an insoluble resin support allows them to be readily separated (by filtration or centrifugation) from excess reagents, soluble reaction by-products, or solvents.

SCAFFOLD

Core portion of a molecule that is common to all members of a combinatorial library.

FLUXIONAL MOLECULES

Molecules that show rapid intramolecular rearrangements among their component atoms. At equilibrium, fluxional molecules can manifest many different isomers and fluctuate rapidly among them (for example, bullvalene).

TAUTOMER

One of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

DECONVOLUTION

The process of optimizing an activity of interest by fractionating a pool with some level of the desired activity to give a set of smaller pools. This strategy can be applied iteratively to identify single members with (ideally) a high level of activity.

VANCOMYCIN

Vancomycin is an antibiotic that acts by binding to cell-wall precursors that terminate in the sequence d-Ala-d-Ala, thereby inhibiting cell-wall synthesis.

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Ramström, O., Lehn, JM. Drug discovery by dynamic combinatorial libraries. Nat Rev Drug Discov 1, 26–36 (2002). https://doi.org/10.1038/nrd704

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