Chemistry Reference
In-Depth Information
Table 7.1
Published examples of
in situ
medicinal chemistry:
in situ
DCC (2006-mid-2007)
and
in situ
Click chemistry (since its inception in 2002-mid-2007).
Biomolecular target
Reversible chemistry Maximum
fragment
size (Da)
a
Analytical
method for hit
identification
a
In situ DCC
Carbonic anhydrase
[15]
Acyl hydrazone
exchange
<
300
ESI-FTICR-MS
Metallo-
-lactamase
[28]
Disulfide exchange
<
200
ESI-MS
Transactivation-response
element of HIV-1
[29]
Imine exchange
<
230
SELEX, HPLC and
MALDI-TOF MS
-1,3-Galactosyltransferase;
-1,4-galactosyltransferase
[30]
Imine exchange
<
250
HPLC
-1,3-Galactosyltransferase
[31]
Imine exchange
<
290
HPLC
Concanavalin A
[32]
Disulfide exchange
∼
220
Quartz crystal
microbalance
Galectin-3;
Viscum album
agglutinin;
Ulex europaeus
agglutinin
[33]
Disulfide exchange
∼
220
Bioassay
Schistosoma japonica
glutathione-
S
-transferase
[34]
Conjugate addition
of thiols to enones
∼
300
HPLC
Calmodulin
[35]
Disulfide exchange
∼
300
HPLC
Subtilisin; albumin
[36]
Disulfide exchange
∼
500
ESI-MS, HPLC
In situ Click chemistry
Acetylcholinesterase
[37 39]
—
∼
230-440
DIOS-MS,
LC-MS-SIM
Carbonic anhydrase
[40, 41, 44]
—
∼
180-350
LC-MS-SIM
HIV-1 protease
[42]
—
∼
190-430
LC-MS-SIM
Plasmodium falciparum
tryptophanyl-tRNA synthetase
[43]
—
NA
NA
Cyclooxygenase-2
[44]
—
NA
NA
a
NA, not available (targets described in published conference abstracts
[43, 44]
).
7.7 Practical Considerations for Drug Discovery Applications
In principle, the
in situ
medicinal chemistry approaches described here have the potential to
circumvent the need to synthesize, characterize and screen each possible library constituent
individually for the purpose of drug discovery. The chemistry, together with the target acting
as a template, permits self-screening owing to selection and/or amplification of the 'best
binders' by molecular recognition events between fragments and the target. This qualitative
description is adequate to convey the concepts of target-guided synthesis; however, in
practice it is essential to know more about the level of product formation to expect as this
is critical to the successful application of analytical methods to detect and identify these
best binder(s).
