Dynamic combinatorial chemistry

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Dynamic combinatorial chemistry (DCC; also known as dynamic covalent chemistry) is a method to the generation of new molecules formed by reversible reaction of simple building blocks under thermodynamic control.[1] The library of these reversibly interconverting building blocks is called a dynamic combinatorial library (DCL).[2] All constituents in a DCL are in equilibrium, and their distribution is determined by their thermodynamic stability within the DCL. The interconversion of these building blocks may involve covalent or non-covalent interactions. When a DCL is exposed to an external influence (such as proteins or nucleic acids), 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.

Protein-directed dynamic combinatorial chemistry[edit]

One of the key developments within the field of DCC is the use of proteins (or other biological macromolecules, such as nucleic acids) to influence the evolution and generation of components within a DCL.[3] 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 and drug discovery.[4]

Scheme illustrating the theory of protein-directed dynamic combinatorial chemistry (DCC).[5]

Reversible covalent reactions[edit]

Types of reversible covalent reactions that have been applied in protein-directed dynamic combinatorial chemistry (DCC).

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, and the components of the DCL must be compatible with proteins.[3][4]

Several reversible reactions have been proposed and/or applied in protein-directed DCC. These included boronate ester formation,[5][6][7] diselenides-disulfides exchange,[8] disulphide formation,[9][10][11] hemithiolacetal formation,[12][13] hydrazone formation,[14][15] imine formation[16][17] and thiol-enone exchange.[18]

Pre-equilibrated DCL[edit]

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, and then diluted into aqueous buffer containing the protein target for selection. Organic based reversible reactions, including Diels-Alder[19] and alkene cross metathesis reactions,[20] have been proposed or applied to protein-directed DCC using this method.

Reversible non-covalent reactions[edit]

Reversible non-covalent reactions, such as metal-ligand coordination,[21][22] has also been applied in protein-directed DCC. This strategy is useful for the investigation of the optimal ligand stereochemistry to the binding site of the target protein.[23]

Enzyme-catalysed reversible reactions[edit]

Enzyme-catalysed reversible reactions, such as protease-catalysed amide bond formation/hydrolysis reactions[24] and the aldolase-catalysed aldol reactions,[25][26] have also been applied to protein-directed DCC.

Analytical methods[edit]

Protein-directed DCC system must be amenable to efficient screening.[3][4] Several analytical techniques have been applied to the analysis of protein-directed DCL. These includes HPLC,[9][13][14][16] mass spectrometry,[6][10][11][15] NMR spectroscopy,[5][7][12] and X-ray crystallography.[27]

Other Applications[edit]

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 materials, foldamers, self-assembling molecules with interlocking architectures and new soft materials.[1] Recently, the application of DCC to detect volatile bioactive compounds, i.e. the amplification and sensing of scent, was proposed in a concept paper.[28]

See also[edit]

References[edit]

  1. ^ a b Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. (Sep 2006). "Dynamic combinatorial chemistry". Chem. Rev. 106 (9): 3652–3711. doi:10.1021/cr020452p. PMID 16967917. 
  2. ^ Lehn, J.-M.; Ramström, O. Generation and screening of a dynamic combinatorial library. PCT. Int. Appl. WO 20010164605, 2001.
  3. ^ a b c 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.
  4. ^ a b c 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.
  5. ^ a b c Leung, I. K. H.; Demetriades, M.; Hardy, A. P.; Lejeune, C.; Smart, T. J.; Szöllössi, A.; Kawamura, A.; Schofield, C. J.; Claridge, T. D. W. (Jan 2013). "NMR reporter ligand screening for inhibitors of 2OG oxygenases". J. Med. Chem. 56 (2): 547–555. doi:10.1021/jm301583m. PMID 23234607. 
  6. ^ a b Demetriades, M.; Leung, I. K. H.; Chowdhury, R.; Chan, M. C.; Yeoh, K. K.; Tian, Y.-M.; Claridge, T. D. W.; Ratcliffe, P. J.; Woon, E. C. Y.; Schofield, C. J. (Jul 2012). "Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors". Angew. Chem. Int. Ed. 51 (27): 6672–6675. doi:10.1002/anie.201202000. PMID 22639232. 
  7. ^ a b Leung, I. K. H.; Brown Jr, T.; Schofield, C. J.; Claridge, T. D. W. (May 2011). "An approach to enzyme inhibition employing reversible boronate ester formation". Med. Chem. Commun. 2 (5): 390–395. doi:10.1039/C1MD00011J. 
  8. ^ Rasmussen, B.; Sørensen, A.; Gotfredsen, H.; Pittelkow, M. (Feb 2014). "Dynamic combinatorial chemistry with diselenides and disulfides in water". Chem. Commun. xx (xx): xxx–xxx. doi:10.1039/C4CC00523F. 
  9. ^ a b Ramström, O.; Lehn, J.-M (Jul 2000). "In situ generation and screening of a dynamic combinatorial carbohydrate library against concanavalin A". ChemBioChem 1 (1): 41–48. doi:10.1002/1439-7633(20000703)1:1<41::AID-CBIC41>3.0.CO;2-L. PMID 11828397. 
  10. ^ a b Liénard, B. M. R.; Selevsek, N.; Oldham, N. J.; Schofield, C. J. (Feb 2007). "Combined mass spectrometry and dynamic chemistry approach to identify metalloenzyme inhibitors". ChemMedChem 2 (2): 175–179. doi:10.1002/cmdc.200600250. PMID 17206734. 
  11. ^ a b Liénard, B. M. R.; Hüting, R.; Lassaux, P.; Galleni, M.; Frére, J.-M.; Schofield, C. J. (Feb 2008). "Dynamic combinatorial mass spectrometry leads to metallo-β-lactamase inhibitors". J. Med. Chem. 51 (3): 684–688. doi:10.1021/jm070866g. PMID 18205296. 
  12. ^ a b Caraballo, R.; Dong, H.; Ribeiro, J. P.; Jiménez-Barbero, J.; Ramström, O. (Jan 2010). "Direct STD NMR identification of β-galactosidase inhibitors from a virtual dynamic hemithioacetal system". Angew. Chem. Int. Ed. 49 (3): 589–593. doi:10.1002/anie.200903920. PMID 20013972. 
  13. ^ a b Clipson, A. J.; Bhat, V. T.; McNae, I.; Caniard, A. M.; Campopiano, D. J.; Greaney, M. F. (Aug 2012). "Bivalent enzyme inhibitors discovered using dynamic covalent chemistry". Chem. Eur. J. 18 (34): 10562–10570. doi:10.1002/chem.201201507. PMID 22782854. 
  14. ^ a b Hochgürtel, M.; Niesinger, R.; Kroth, H.; Piecha, D.; Hofmann, M. W.; Krause, S.; Schaaf, O.; Nicolau, C.; Eliseev, A. V. (Jan 2003). "Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selective pressure of the biological target". J. Med. Chem. 46 (3): 356–358. doi:10.1021/jm025589m. PMID 12540234. 
  15. ^ a b Sindelar, M.; Lutz, T. A.; Petrera, M.; Wanner, K. T. (Feb 2013). "Focused pseudostatic hydrazone libraries screened by mass spectrometry binding assay: optimizing affinities toward γ-aminobutyric acid transporter 1". J. Med. Chem. 56 (3): 1323–1340. doi:10.1021/jm301800j. PMID 23336362. 
  16. ^ a b Zameo, S.; Vauzeilles, B.; Beau, J.-M. (Dec 2006). "Direct composition analysis of a dynamic library of imines in an aqueous medium". Eur. J. Org. Chem. 2006 (24): 5441–5444. doi:10.1002/ejoc.200600859. 
  17. ^ Herrmann, A. (Aug 2009). "Dynamic mixtures and combinatorial libraries: imines as probes for molecular evolution at the interface between chemistry and biology". Org. Biomol. Chem. 7 (16): 3195–3204. doi:10.1039/B908098H. PMID 19641772. 
  18. ^ Shi, B.; Stevenson, R.; Campopiano, D. J.; Greaney, M. F. (Jul 2006). "Discovery of glutathione S-transferase inhibitors using dynamic combinatorial chemistry". J. Am. Chem. Soc. 128 (26): 8459–8467. doi:10.1021/ja058049y. PMID 16802811. 
  19. ^ Boul, P. J.; Reutenauer, P.; Lehn, J.-M. (Jan 2005). "Reversible Diels-Alder reactions for the generation of dynamic combinatorial libraries". Org. Lett. 7 (1): 15–18. doi:10.1021/ol048065k. PMID 15624966. 
  20. ^ Poulsen, S.-A.; Bornaghi, L. F. (May 2006). "Fragment-based drug discovery of carbonic anhydrase II inhibitors by dynamic combinatorial chemistry utilizing alkene cross metathesis". Bioorg. Med. Chem. 14 (10): 3275–3284. doi:10.1016/j.bmc.2005.12.054. PMID 16431113. 
  21. ^ Sakai, S.; Shigemasa, Y.; Sasaki, T. (Nov 1997). "A self-adjusting carbohydrate ligand for GalNAc specific lectins". Tetrahedron Lett. 38 (47): 8145–8148. doi:10.1016/S0040-4039(97)10187-3. 
  22. ^ Sakai, S.; Shigemasa, Y.; Sasaki, T. (1999). "Iron(II)-assisted assembly of trivalent GalNAc clusters and their interactions with GalNAc-specific lectins". Bull. Chem. Soc. Jpn. 72: 1313–1319. doi:10.1246/bcsj.72.1313. 
  23. ^ Kilpin, K. J.; Dyson, P. J. (Feb 2013). "Enzyme inhibition by metal complexes: concepts, strategies and applications". Chem. Sci. 4: 1410–1419. doi:10.1039/C3SC22349C. 
  24. ^ Swann, P. G.; Casanova, R. A.; Desai, A.; Frauenhoff, M. M.; Urbancic, M.; Slomczynska, U.; Hopfinger, A. J.; Le Breton, G. C.; Venton, D. L. (1996). "Nonspecific protease-catalyzed hydrolysis/synthesis of a mixture of peptides: product diversity and ligand amplification by a molecular trap". Biopolymers 40 (6): 617–625. doi:10.1002/(sici)1097-0282(1996)40:6<617::aid-bip3>3.0.co;2-z. PMID 9140201. 
  25. ^ Lins, R. J.; Flitsch, S. L.; Turner, N. J.; Irving, E.; Brown, S. A. (Sep 2002). "Enzymatic generation and in situ screening of a dynamic combinatorial library of sialic acid analogues". Angew. Chem. Int. Ed. 41 (18): 3405–3407. doi:10.1002/1521-3773(20020916)41:18<3405::AID-ANIE3405>3.0.CO;2-P. PMID 12298046. 
  26. ^ Lins, R. J.; Flitsch, S. L.; Turner, N. J.; Irving, E.; Brown, S. A. (Jan 2004). "Generation of a dynamic combinatorial library using sialic acid aldolase and in situ screening against wheat germ agglutinin". Tetrahedron 60 (3): 771–780. doi:10.1016/j.tet.2003.11.062. 
  27. ^ Valade, A.; Urban, D.; Beau, J.-M. (Jan–Feb 2007). "Two galatosyltransferases’ selection of different binders from the same uridine-based dynamic combinatorial library". J. Comb. Chem. 9 (1): 1–4. doi:10.1021/cc060033w. PMID 17206823. 
  28. ^ Herrmann, A. (Jul 2012). "Dynamic Mixtures: Challenges and Opportunities for the Amplification and Sensing of Scents". Chem. Eur. J. 18 (28): 8568–8577. doi:10.1002/chem.201200668. PMID 22588709. 

External links[edit]