Biomedical Engineering Reference
In-Depth Information
N
COOMe
HO
O
O
HO
O
HO
NH
HN
OH
K
d
= 100 μM
O
K
d
= 280 μM
MeO
OMe
K
d
= 17 mM
OMe
K
d
= 2 μM
N
HO
NH
O
HO
O
O
HN
OH
N
O
O
O
K
d
= 15 nM
K
d
= 49 nM
MeO
OMe
N
OMe
(a)
MMP3 inhibitors
FKBP inhibitors
O
O
O
O
O
O
S
COOH
COOH
S
S
N
N
N
N
N
O
O
O
COOH
COOH
O
O
HO
HO
HN
(b)
Thymidylate synthase inhibitors
COOH
FIGURE 4.3
Illustration of the two principles applied in fragment-based screening. (a) Fragment linking:
two fragments were identii ed as very weak inhibitors of matrix metalloproteinase 3 (MMP3), but by link-
ing a highly potent lead compound was identii ed. Similarly, a potent inhibitor of the FKBP was achieved by
linking two weaker inhibitors. (b) Fragment evolution: a very potent inhibitor of thymidylate synthase was
identii ed.
Alternatively, the knowledge of the identii ed fragments is used to develop hypotheses on how to
expand the fragment by additional interactions in the active site of the protein. This “evolution”
then leads to compounds with improved binding, which can be further optimized (Figure 4.3). The
fragment “evolution” principle is probably most often applicable and is an elegant demonstration of
structure-based drug design (see Chapter 2).
Fragment-based drug design is a highly promising strategy that is widely applied both in indus-
try and at academic institutions. It is still limited to studies of soluble proteins, as easy access to
detailed structural information is required. Moreover, due to the novelty of the approach, there are
still no drugs on the market, which are developed by fragment-based screening.
4.2.2 A
PPLYING
S
MALL
M
OLECULES
IN
B
IOLOGY
Extracts from natural sources have been used in the treatment of diseases since ancient times, but
in the early nineteenth century, isolated natural products became available and have ever since been
used as biological probes and drugs. The i rst isolated natural products used as drugs were alkaloids
such as morphine, quinine, and codeine (see Chapter 6), and later derivatives of natural products,
