24
Bioorganic Chemistry
R
1
H
2
N
N
Positional scanning deconvolution:
30 sublibraries synthesized simultaneously:
10 possible
10 possible 10 possible
=
1000 total peptides
N
H
OOO
OH
H
R
2
R
3
R1-N-N
N-R2-N
N-N-R3
R1
=
ALA
GLY
SER
THR
PRO
TYR
LY S
GLN
ARG
ASP
R2
=
ALA
GLY
SER
THR
PRO
TYR
LY S
GLN
ARG
ASP
R3
=
ALA
GLY
SER
THR
PRO
TYR
LY S
GLN
ARG
ASP
N
=
random mixture
of 10 amino acids
N
=
random mixture
of 10 amino acids
N
=
random mixture
of 10 amino acids
Winning mixture at
each position indicated
with a box
Target selected for
resynthesis: GLY-PRO-ASP
Fig. 18
Deconvolution of a three-position peptide library using the positional scanning
approach.
be more than one clear winner at each
position in the oligomer. If this is the case,
then multiple resyntheses are warranted.
For
example,
if
there
are
two
active
sublibraries at the ±rst position, two at the
second, and three at the third, then 2
×
2
×
3or12newindividualmoleculesshouldbe
synthesized as individual species to assess
for activity.
A second approach for deconvolution
is the method of iterative deconvolution
(Fig. 19). This also uses the technique
of having multiple random positions and
individual ±xed positions to identify indi-
vidual active species from large libraries.
Whereas positional scanning allows one
to simultaneously synthesize and assay
all sublibraries at once, iterative decon-
volution requires a series of alternating
synthesis and assay steps. Using the ex-
ample of the tripeptide library above,
deconvolution would begin by making
a collection of 10 sublibraries in which
the ±rst position is ±xed and the second
two positions have random amino acids.
Therefore, one would have a sublibrary of
10 elements. Each of these 10 elements
wou
ldbeassayedandthemos
tac
t
ivee
l
-
ement would identify the speci±c amino
acid at that position. A new collection of
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