Biomedical Engineering Reference
In-Depth Information
Biologically active
natural product
Target-oriented synthesis
Single target synthesis
Identification of a biological target
Known biologically
active molecule
Hypothesis driven
Combinatorial chemistry
Structurally focused library synthesis
Chemical target optimization
Known biological
target
Fragment-based methods
Single target synthesis
Chemical target identification
Identification of
chemical targets
Identification of
biological targets
Discovery based
Diversity-oriented synthesis
Structurally diverse library synthesis
FIGURE 15.1
Scope of biased and unbiased approaches.
of a related analogue either by linking two binding subunits or by altering the
peripheral functionalities of the main scaffold.
15.3.1. Fragment-Based Drug Discovery
In 1996, Fesik and coworkers introduced a novel concept based on NMR (nuclear
magnetic resonance) spectroscopy to discover small molecules that bind tightly to the
protein FKBP [16,17]. The strategy initially named “SAR by NMR” consisted of
identifying by NMR lowmolecular weight fragments that bind to neighboring sites of
the protein with submillimolar affinities. A more potent FKBP binding small
molecule was then obtained by tethering the two fragments (Scheme 15.1, Eq. 15.1).
Mass spectrometry, X-ray crystallography, and computational methods have also
been used to rationalize structure-based design of small molecule to improve the
selection of fragments. However, the experimental design is often biased toward
Fragments
O
HO
Stable linker
HN
OH
O
O
O
K
d
= 100
μ
M
HN
OH
N
O
OMe
O
FKBP binding small molecule
K
d
= 19 nM
O
(Eq. 15.1)
N
O
O
O
MeO
OMe
OMe
MeO
OMe
OMe
K
d
= 2
μ
M
R
2
Labile bond
N
Stable bond
NH
(Eq. 15.2)
CA
NaBH
3
C
N
R
1
CHO
R
2
NH
2
Library of aldehydes and amines
R
1
O
S
NH
2
O
O
S
NH
2
O
CA binding small molecule
K
d
= n.d.
NH
2
Stable ring
N
N
N
N
(Eq. 15.3)
N
H
AChE
R
1
N
3
R
2
AChE binding small molecule
K
d
= 77-410 fM
Library of alkynes and azides
NH
2
R
1
R
2
SCHEME 15.1
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