The impact of the size of dynamic combinatorial libraries on the detectability of molecular recognition induced amplification

Journal of the American Chemical Society

Volumn 132, Issue 17, 2010, Pages 5984-5986

  Ludlow, R Frederick ^a   Otto, Sijbren ^a  

^a UNIVERSITY OF GRONINGEN   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING AFFINITIES; BUILDING BLOCKES; DETECTABILITY; DYNAMIC COMBINATORIAL LIBRARY; ON DYNAMICS;

AMPLIFICATION; BINDERS; BINDING ENERGY; BIOASSAY; BIOCHIPS; MOLECULAR BIOLOGY; MOLECULAR RECOGNITION;

LIBRARIES;

ARTICLE; BINDING AFFINITY; COMBINATORIAL CHEMISTRY; COMBINATORIAL LIBRARY; GENE AMPLIFICATION; MOLECULAR DYNAMICS; MOLECULAR RECOGNITION; PROBABILITY;

COMBINATORIAL CHEMISTRY TECHNIQUES; COMPUTER SIMULATION; LIGANDS; MODELS, CHEMICAL; SMALL MOLECULE LIBRARIES; SOFTWARE;

EID: 77951697972     PISSN: 00027863     EISSN: 15205126     Source Type: Journal    
DOI: 10.1021/ja1013689     Document Type: Article

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41. In these simulations we do not consider any chemical structure, only template binding affinities and equilibrium constants describing the formation of library members from the building blocks.
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45. Note that the size of the data set needed for obtaining statistically significant guidance on the issue of library size presents a huge challenge to any experimental approach of this subject.
46. This implies a lower absolute detection threshold for larger libraries. However, within identical experimental conditions (same template and total building block concentration) the absolute threshold for a 16 building block library differs from that of a 4 building block library only by a factor of 7 (Figure S1). Hence, injecting a 7-fold larger volume of sample for the 16 building block library would give effectively the same absolute detection threshold.
47. Repeating the analysis with a detection threshold of amplification effects of 10% of the concentration of the most abundant library member gave comparable results. See Figure S2.
48. While strong binders will generally have higher amplification factors (5) these may still not be sufficient to make these compounds detectable in cases where the concentration of the particular library member in the absence of the template was very low (as is, for example, the case for a higher oligomer containing several copies of the same building block).
49. The average was taken of 100 separate simulations that differed only in the randomly assigned template binding affinities.
50. Given the less than perfect correlation between amplification factors and binding affinities in most DCLs (6, 7) it is advisable to follow up on several of the most amplified compounds. Here we arbitrarily decided to consider the three most amplified compounds.
51. The statistically expected affinity refers to the highest affinity based on n random draws from a normal distribution (mean log K = 2; standard deviation = 1), where n = the number of detectable library members. See
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53. More detailed experimental recommendations are provided in the Supporting Information.
54. Our simulations are based on the assumption that binding constants of the library members obey a log normal distribution. This assumption may not hold when combining structurally very different building blocks.