In Situ Fragment-based Medicinal Chemistry: Screening by Mass Spectrometry - Fragment-Based Drug Discovery - page 164

presence of
template

absence of
template

-4 -2 0 2 4 6

log K

Figure 7.4 Histograms representing the composition of a continuous DCL in the absence and
presence of a template and a typical simulated DCL containing 10 000 compounds (bars). Bars
are labelled with the number of compounds in the affinity class. Reprinted with permission
from Corbett, P.T., et al . Org. Lett . 2004, 6 , 1825-1827. Copyright (2004) American Chemical
Society.

60%

4.0%

×

×

50%

3.0%

× ×

× ×

2.0%

× × × ×

40%

1.0%

0.0%

× × ×

10 000 100 000 1 000 000

30%

20%

×

× × × × × × × × × × × × × ×

10%

0%

1 100 10 000 1 000 000

Number of compounds in simulated DCL

Figure 7.5 Yields of the best binders as a function of library size. Each data point represents
the average from 100 simulated DCLs. Reprinted with permission from Corbett, P.T., et al .
Org. Lett . 2004, 6 , 1825-1827. Copyright (2004) American Chemical Society.

the target biomolecule, aqueous buffer, fragment building blocks and noncovalent target-
ligand complexes. A major difference is that in situ Click chemistry, unlike in situ DCC,
has minimal background reaction in the bulk solution. In situ Click chemistry additionally
presents a far tougher screening challenge owing to the very low level of conversion of
fragments to potential binding ligands. At present there is no material in the primary liter-
ature that describes the theoretical level of product conversion to expect; it has, however,