Key Points
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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.
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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.
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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.
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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.
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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:
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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.
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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.
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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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References
Furka, A. in Notarised Report (Hungary, 1982).
Terrett, N. K. Combinatorial Chemistry (Oxford Univ. Press, Oxford, 1998).
Fenniri, H. (ed) Combinatorial Chemistry (Oxford Univ. Press, Oxford, 2000).
Ganesan, A. Strategies for the dynamic integration of combinatorial synthesis and screening. Angew. Chem. Int. Edn Engl. 37, 2828–2831 (1998).
Lehn, J.-M. Dynamic combinatorial chemistry and virtual combinatorial libraries. Chem. Eur. J. 5, 2455–2463 (1999).
Timmerman, P. & Reinhoudt, D. N. A combinatorial approach to synthetic receptors. Adv. Mater. 11, 71–74 (1999).
Klekota, B. & Miller, B. L. Dynamic diversity and small-molecule evolution: a new paradigm for ligand identification. Trends Biotechnol. 17, 205–209 (1999).
Cousins, G. R. L., Poulsen, S. A. & Sanders, J. K. M. Molecular evolution: dynamic combinatorial libraries, autocatalytic networks and the quest for molecular function. Curr. Opin. Chem. Biol. 4, 270–279 (2000).
Lehn, J.-M. & Eliseev, A. V. Dynamic combinatorial chemistry. Science 291, 2331–2332 (2001).
Lehn, J.-M. in Essays in Contemporary Chemistry. From Molecular Structure Towards Biology (eds Quinckert, G. & Kisakürek, M. V.) 307–326 (Verlag Helvetica Chimica Acta, Zürich, 2001).
Fischer, E. Einfluss der Configuration auf die Wirkung der Enzyme. Chem. Ber. 27, 2985–2993 (1894).
Huc, I. & Lehn, J.-M. Virtual combinatorial libraries: dynamic generation of molecular and supramolecular diversity by self-assembly. Proc. Natl Acad. Sci. USA 94, 2106–2110 (1997).The application of a dynamic combinatorial library to a biological target molecule.
Hasenknopf, B., Lehn, J.-M., Kneisel, B. O., Baum, G. & Fenske, D. Self-assembly of a circular double helicate. Angew. Chem. Int. Edn Engl. 35, 1838–1840 (1996).
Baxter, P. N. W., Lehn, J. M. & Rissanen, K. Generation of an equilibrating collection of circular inorganic copper(I) architectures and solid-state stabilization of the dicopper helicate component. J. Chem. Soc. Chem. Commun. 1323–1324 (1997).
Sakai, S., Shigemasa, Y. & Sasaki, T. A self-adjusting carbohydrate ligand for GalNAc specific lectins. Tetrahedron Lett. 38, 8145–8148 (1997).
Albrecht, M., Blau, O. & Fröhlich, R. An expansible metalla-cryptand as a component of supramolecular combinatorial library formed from di(8-hydroxyquinoline) ligands and gallium(III) or zinc(II) ions. Chem. Eur. J. 5, 48–56 (1999).
Albrecht, M., Schneider, M. & Röttele, H. Template-directed self-recognition of alkyl-bridged bis(catechol) ligands in the formation of helicate-type complexes. Angew. Chem. Int. Edn Engl. 38, 557–559 (1999).
Huc, I., Krische, M. J., Funeriu, D. P. & Lehn, J.-M. Dynamic combinatorial chemistry: substrate H-bonding directed assembly of receptors based on bipyridine-metal complexes. Eur. J. Inorg. Chem. 1415–1420 (1999).
Baum, G., Constable, E. C., Fenske, D., Housecroft, C. E. & Kulke, T. Chiral 1,2-ethanediyl-spaced quaterpyridines give a library of cyclic and double helicates with copper(I). J. Chem. Soc. Chem. Commun. 195–196 (1999).
Baxter, P. N. W., Khoury, R. G., Lehn, J.-M., Baum, G. & Fenske, D. Adaptive self-assembly: environment-induced formation and reversible switching of polynuclear metallocyclophanes. Chem. Eur. J. 6, 4140–4148 (2000).
Umemoto, K., Yamaguchi, K. & Fujita, M. Molecular paneling via coordination: guest-controlled assembly of open cone and tetrahedron structures from eight metals and four ligands. J. Am. Chem. Soc. 122, 7150–7151 (2000).
Yamanoi, Y. et al. Dynamic assembly of coordination boxes from (en)Pd(II) unit and a rectangular panel-like ligand: NMR, CSI-MS, and X-ray studies. J. Am. Chem. Soc. 123, 980–981 (2001).
Calama, M. C. et al. Libraries of noncovalent hydrogen-bonded assemblies — combinatorial synthesis of supramolecular systems. J. Chem. Soc. Chem. Commun. 1021–1022 (1998).Demonstration of hydrogen-bonded dynamic libraries.
Calama, M. C., Timmerman, P. & Reinhoudt, D. N. Guest-templated selection and amplification of a receptor by noncovalent combinatorial synthesis. Angew. Chem. Int. Edn Engl. 39, 755–758 (2000).
Cardullo, F. et al. Covalent capture of dynamic hydrogen-bonded assemblies. J. Chem. Soc. Chem. Commun. 367–368 (2000).
Hof, F., Nuckolls, C. & Rebek, J. Jr. Diversity and selection in self-assembled tetrameric capsules. J. Am. Chem. Soc. 122, 4251–4252 (2000).
Klekota, B., Hammond, M. H. & Miller, B. L. Generation of novel DNA-binding compounds by selection and amplification from self-assembled combinatorial libraries. Tetrahedron Lett. 38, 8639–8642 (1997).The application of metal-coordinated dynamic combinatorial libraries to DNA binding.
Berl, V., Huc, I., Lehn, J.-M., DeCian, A. & Fischer, J. Induced fit selection of a barbiturate receptor from a dynamic structural and conformational/configurational library. Eur. J. Org. Chem. 3089–3094 (1999).
Klekota, B. & Miller, B. L. Selection of DNA-binding compounds via multistage molecular evolution. Tetrahedron 55, 11687–11697 (1999).
Polyakov, V. A., Nelen, M. I., Nazarpack-Kandlousy, N., Ryabov, A. D. & Eliseev, A. V. Imine exchange in O-aryl and O-alkyl oximes as a base reaction for aqueous 'dynamic' combinatorial libraries. A kinetic and thermodynamic study. J. Phys. Org. Chem. 12, 357–363 (1999).
Cousins, G. R. L., Poulsen, S.-A. & Sanders, J. K. M. Dynamic combinatorial libraries of pseudo-peptide hydrazone macrocycles. J. Chem. Soc. Chem. Commun. 1575–1576 (1999).
Ro, S., Rowan, S. J., Pease, A. R., Cram, D. J. & Stoddart, J. F. Dynamic hemicarcerands and hemicarceplexes. Org. Lett. 2, 2411–2414 (2000).
Bunyapaiboonsri, T. et al. Dynamic deconvolution of a pre-equilibrated dynamic combinatorial library of acetylcholinesterase inhibitors. ChemBioChem 2, 438–444 (2001).Use of deconvolution to identify active components from a dynamic combinatorial library.
Goral, V., Nelen, M. I., Eliseev, A. V. & Lehn, J.-M. Double-level 'orthogonal' dynamic combinatorial libraries on transition metal template. Proc. Natl Acad. Sci. USA 98, 1347–1352 (2001).
Cousins, G. R. L., Furlan, R. L. E., Ng, Y.-F., Redman, J. E. & Sanders, J. K. M. Identification and isolation of a receptor for N-methyl alkylammonium salts: molecular amplification in a pseudo-peptide dynamic combinatorial library. Angew. Chem. Int. Edn Engl. 40, 423–428 (2001).Demonstration of dynamic receptor libraries.
Epstein, D. M. et al. Chloroform-soluble Schiff-base Zn(II) or Cd(II) complexes from a dynamic combinatorial library. Inorg. Chem. 40, 1591–1596 (2001).
Star, A., Goldberg, I. & Fuchs, B. Diazadioxadecalin and salen podands and macrocycles within dynamic combinatorial virtual libraries: structure, prototopy, complexation and enantioselective catalysis. J. Organomet. Chem. 630, 67–77 (2001).
Star, A., Goldberg, I. & Fuchs, B. Dioxadiazadecalin/salen tautomeric macrocycles and complexes: prototypal dynamic combinatorial virtual libraries. Angew. Chem. Int. Edn Engl. 39, 2685–2689 (2000).
Brady, P. A., Bonar-Law, R. P., Rowan, S. J., Suckling, C. J. & Sanders, J. K. M. 'Living' macrolactonisation: thermodynamically-controlled cyclisation and interconversion of oligocholates. J. Chem. Soc. Chem. Commun. 319–320 (1996).
Rowan, S. J., Brady, P. A. & Sanders, J. K. M. Structure-directed synthesis under thermodynamic control: macrocyclic trimers from Cinchona alkaloids. Angew. Chem. Int. Edn Engl. 35, 2143–2145 (1996).
Rowan, S. J., Hamilton, D. G., Brady, P. A. & Sanders, J. K. M. Automated recognition, sorting, and covalent self-assembly by predisposed building blocks in a mixture. J. Am. Chem. Soc. 119, 2578–2579 (1997).
Rowan, S. J. & Sanders, J. K. M. Building thermodynamic combinatorial libraries of quinine macrocycles. J. Chem. Soc. Chem. Commun. 1407–1408 (1997).
Rowan, S. J., Lukeman, P. S., Reynolds, D. J. & Sanders, J. K. M. Engineering diversity into dynamic combinatorial libraries by use of a small flexible building-block. New J. Chem. 22, 1015–1018 (1998).
Monvisade, P., Hodge, P. & Ruddick, C. L. Synthesis of soluble combinatorial libraries of crown ether–ester analogues via the cyclodepolymerisation of linear polyesters. J. Chem. Soc. Chem. Commun. 1987–1988 (1999).
Brändli, C. & Ward, T. R. Libraries via metathesis of internal olefins. Helv. Chim. Acta 81, 1616–1621 (1998).
Giger, T., Wigger, M., Audetat, S. & Benner, S. A. Libraries for receptor-assisted combinatorial synthesis (RACS). The olefin metathesis reaction. SYNLETT 688–691 (1998).
Hamilton, D., Feeder, N., Teat, S. & Sanders, J. Reversible synthesis of π-associated [2]catenanes by ring-closing metathesis: towards dynamic combinatorial libraries of catenanes. New J. Chem. 22, 1019–1021 (1998).
Kidd, T. J., Leigh, D. A. & Wilson, A. J. Organic 'magic rings': the hydrogen bond-directed assembly of catenanes under thermodynamic control. J. Am. Chem. Soc. 121, 1599–1600 (1999).
Nicolaou, K. C. et al. Target-accelerated combinatorial synthesis and discovery of highly potent antibiotics effective against vancomycin-resistant bacteria. Angew. Chem. Int. Edn Engl. 39, 3823–3828 (2000).The use of dynamic combinatorial libraries to generate and identify potent antibiotics.
Katz, B. A., Finer-Moore, J., Mortezaei, R., Rich, D. H. & Stroud, R. M. Episelection: novel Ki approximately nanomolar inhibitors of serine proteases selected by binding or chemistry on an enzyme surface. Biochemistry 34, 8264–8280 (1995).
Hioki, H. & Clark Still, W. Chemical evolution: a model system that selects and amplifies a receptor for the tripeptide (d)Pro(l)Val(d)Val. J. Org. Chem. 63, 904–905 (1998).
Ramström, O. & Lehn, J.-M. In situ generation and screening of a dynamic combinatorial carbohydrate library against concanavalin A. ChemBioChem 1, 41–47 (2000).
Otto, S., Furlan, R. L. E. & Sanders, J. K. M. Dynamic combinatorial libraries of macrocyclic disulfides in water. J. Am. Chem. Soc. 122, 12063–12064 (2000).
Eliseev, A. & Nelen, M. Use of molecular recognition to drive chemical evolution. 1. Controlling the composition of an equilibrating mixture of simple arginine receptors. J. Am. Chem. Soc. 119, 1147–1148 (1997).Describes an iterative process to increase the formation of a library constituent.
Berl, V., Krische, M. J., Huc, I., Lehn, J.-M. & Schmutz, M. Template-induced and molecular recognition directed hierarchical generation of supramolecular assemblies from molecular strands. Chem. Eur. J. 6, 1938–1946 (2000).
Moore, J. S. & Zimmerman, N. W. 'Masterpiece' copolymer sequences by targeted equilibrium-shifting. Org. Lett. 2, 915–918 (2000).
Nelson, S. M., Knox, C. V., McCann, M. & Drew, M. G. B. Metal-ion-controlled transamination in the synthesis of macrocyclic Schiff-base ligands. Part 1. Reactions of 2,6-diacetylpyridine and dicarbonyl compounds with 3,6-dioxaoctane-1,8-diamine. J. Chem. Soc. Dalton Trans. 1669–1677 (1981).
Nelson, S. M. Binuclear complexes of macrocyclic Schiff base ligands as hosts for small substrate molecules. Inorg. Chim. Acta 62, 39–50 (1982).
Goodwin, J. T. & Lynn, D. G. Template-directed synthesis: use of a reversible reaction. J. Am. Chem. Soc. 114, 9197–9198 (1992).
Krämer, R., Lehn, J.-M. & Marquis-Rigault, A. Self-recognition in helicate self-assembly: spontaneous formation of helical metal complexes from mixtures of ligands and metal ions. Proc. Natl Acad. Sci. USA 90, 5394–5398 (1993).
Hasenknopf, B., Lehn, J.-M., Boumediene, N., Dupont-Gervais, A. & Van Dorsselaer, A. Self-assembly of tetra- and hexanuclear circular helicates. J. Am. Chem. Soc. 119, 10956–10962 (1997).
Brady, P. A. & Sanders, J. K. M. Thermodynamically-controlled cyclization and interconversion of oligocholates — metal-ion templated living macrolactonisation. J. Chem. Soc. Perkin Trans. 1, 3237–3253 (1997).
Swann, P. G. et al. Nonspecific protease-catalysed hydrolysis/synthesis of a mixture of peptides: product diversity and ligand amplification by a molecular trap. Biopolymers 40, 617–625 (1996).
Case, M. A. & McLendon, G. L. A virtual library approach to investigate protein folding and internal packing. J. Am. Chem. Soc. 122, 8089–8090 (2000).
Eliseev, A. V. & Nelen, M. I. Use of molecular recognition to drive chemical evolution: mechanisms of an automated genetic algorithm implementation. Chem. Eur. J. 4, 825–834 (1998).
Lee, S. B., Hwang, S., Chung, D. S., Yun, H. & Hong, J.-I. Guest-induced reorganization of a self-assembled Pd(II) Complex. Tetrahedron Lett. 39, 873–876 (1998).
Hiraoka, S. & Fujita, M. Guest-selected formation of Pd(II)-linked cages from a prototypical library. J. Am. Chem. Soc. 121, 10239–10240 (1999).
Hiraoka, S., Kubota, Y. & Fujita, M. Self- and hetero-recognition in the guest-controlled assembly of Pd(II)-linked cages from two different ligands. J. Chem. Soc. Chem. Commun. 1509–1510 (2000).
Furlan, R. L. E., Cousins, G. R. L. & Sanders, J. K. M. Molecular amplification in a dynamic combinatorial library using non-covalent interactions. J. Chem. Soc. Chem. Commun. 1761–1762 (2000).
Sussmuth, R. D. & Jung, G. Impact of mass spectrometry on combinatorial chemistry. J. Chromatogr. B Biomed. Sci. Appl. 725, 49–65 (1999).
Henrichsen, D. et al. Bioaffinity NMR. Angew. Chem. Int. Edn Engl. 38, 98–101 (1999).
Lehn, J.-M. in Supramolecular Polymers (ed. Ciferri, A.) 615–641 (Marcel Dekker, Inc., New York, 2000).
Lehn, J.-M. in Supramolecular Science: Where it is and Where it is Going (eds Ungaro, R. & Dalcanale, E.) 273–286 (Kluwer Academic, Dordrecht, The Netherlands, 1999).
Llull, R. in Ars Magna (1305–1308).
Saporta, M. Composition N°1 (Seuil, Paris, 1962).
Queneau, R. Cent Mille Milliards de Poèmes (Gallimard, Paris, 1961).
Boulez, P. ...Explosante-Fixe... (1993).
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Glossary
- COMBINATORIAL CHEMISTRY
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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
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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
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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
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Core portion of a molecule that is common to all members of a combinatorial library.
- FLUXIONAL MOLECULES
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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
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One of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
- DECONVOLUTION
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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
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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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DOI: https://doi.org/10.1038/nrd704
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