What are the limits to the size of effective dynamic combinatorial libraries?

Organic Letters

Volumn 6, Issue 11, 2004, Pages 1825-1827

  Corbett, Peter T ^a   Otto, Sijbren ^a   Sanders, Jeremy K M ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMICAL COMPOUND;

ARTICLE; BINDING AFFINITY; COMBINATORIAL LIBRARY; COMPUTER SIMULATION; CONCENTRATION (PARAMETERS); MODEL; MOLECULAR DYNAMICS;

EID: 2942594718     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol049398k     Document Type: Article

References (16)

1. Reviews: (a) Otto, S. Curr. Opin. Drug Discovery Dev. 2003, 6, 509-520. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2002, 6, 295-321. (c) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898-952. (d) Ramström, O.; Bunyapaboonsri, T.; Lohmann, S.; Lehn, J.-M. Biochim. Biophys. Acta 2002, 1572, 178-186. (e) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Drug Discovery Today 2002, 7, 117-125.
2. Reviews: (a) Otto, S. Curr. Opin. Drug Discovery Dev. 2003, 6, 509-520. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2002, 6, 295-321. (c) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898-952. (d) Ramström, O.; Bunyapaboonsri, T.; Lohmann, S.; Lehn, J.-M. Biochim. Biophys. Acta 2002, 1572, 178-186. (e) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Drug Discovery Today 2002, 7, 117-125.
3. Reviews: (a) Otto, S. Curr. Opin. Drug Discovery Dev. 2003, 6, 509-520. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2002, 6, 295-321. (c) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898-952. (d) Ramström, O.; Bunyapaboonsri, T.; Lohmann, S.; Lehn, J.-M. Biochim. Biophys. Acta 2002, 1572, 178-186. (e) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Drug Discovery Today 2002, 7, 117-125.
4. Reviews: (a) Otto, S. Curr. Opin. Drug Discovery Dev. 2003, 6, 509-520. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2002, 6, 295-321. (c) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898-952. (d) Ramström, O.; Bunyapaboonsri, T.; Lohmann, S.; Lehn, J.-M. Biochim. Biophys. Acta 2002, 1572, 178-186. (e) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Drug Discovery Today 2002, 7, 117-125.
5. Reviews: (a) Otto, S. Curr. Opin. Drug Discovery Dev. 2003, 6, 509-520. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2002, 6, 295-321. (c) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898-952. (d) Ramström, O.; Bunyapaboonsri, T.; Lohmann, S.; Lehn, J.-M. Biochim. Biophys. Acta 2002, 1572, 178-186. (e) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Drug Discovery Today 2002, 7, 117-125.
6. Some systems - for example, DCLs of macrocycles, where there is no clearly defined limit to the size of the macrocycles - contain a very large number of compounds. However, the majority of those compounds (e.g., very large macrocycles) are likely to be present at such low concentrations in the absence of template (to the extent that all of these compounds together may only account for a small fraction of the library) that even if they were to be strongly amplified, this would go unnoticed. Detectable amplification is likely to be confined to the relatively small set of compounds with appreciable concentrations.
7. Moore, J. S.; Zimmerman, N. W. Org. Lett. 2000, 2, 915-918.
8. The geometric mean, as the relevant distributions are log-normal.
9. All of the models discussed in this paper apply equally well to DCLs where the library members act as the guests, and the template as a host.
10. 3 variation of this value does not significantly affect the main conclusions of this paper. Larger values of this mean will simply result in an increase in the mean and highest binding constants in the templated library. In experimental systems, such an elevated mean could arise from the use of a carefully chosen set of building blocks, with features that are likely to be complementary to the template.
11. (a) Grote, Z.; Scopelliti, R.; Severin, K. Angew. Chem., Int. Ed, 2003, 42, 3821-3825.
12. (b) Severin, K. Chem. Eur. J., in press.
13. Corbett, P. T.; Otto, S.; Sanders, J. K. M. Chem. Eur. J., in press.
14. For DCLs with 10 000 or more compounds, explicitly simulating each of the library members individually became too computationally demanding, so an approximation was introduced. For each of these DCLs, a threshold log K was chosen. Library members with binding constants above the threshold (approximately 1 in 100) were all included in the simulation. Only one in n of those with binding constants below the threshold were included, but the equilibrium constants for the formation of those library members were set so as to increase their concentration in the template-free library by a factor of n. In all of these cases, n was chosen such that the subthreshold part of the library was represented by 100 compounds.
15. An alternative approach is to consider the expected binding affinity of the best compound in the DCL, and take the area of the "tail" of the graph for the shifted equilibrium above that value to be the concentration of the best binder. This method generally overestimates concentrations of the top compounds-but never by more than a factor of 2.
16. Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Science 2002, 297, 590-593.