Biomedical Engineering Reference
In-Depth Information
the scaffolds associated with anti-AIDS activity [111]. Such selected scaffolds can
serve as a basis to help chemists to identify optimal scaffold replacements. Ertl
recently described a system, which was implemented at a pharmaceutical company,
to identify bioisosteric scaffolds in a database with more than 7000 scaffolds extracted
from bioactive compounds [112]. In this work, Ertl present an excellent discussion
of the computational approaches that have been developed over the years in the field
of automatic scaffold replacement [112].
According to a recent analysis of the public databases annotated with biological
activity (BindingDB [113], ChEMBL [106], and PubChem [77]), the number of
different scaffolds calculated for active molecules against human targets is more than
76,000 [114]. Several other scaffold analyses of different data sets are described in
recent excellent works of scaffold analysis [107,114,115].
Scaffold content analyses of compound collections usually report themost frequent
scaffolds found in the databases. To illustrate this point, Figure 10.5 shows the five
most frequent scaffolds found in four types of compound collections: approved drugs,
Approved drugs
Natural products
O
O
O
O
O
RYLFV
143 (9.6%)
7Y26M
29 (1.9%)
6BM8X
22 (1.5%)
O
RYLFV
76 (3.1%)
YSB4M
58 (2.3%)
Q874P
44 (1.8%)
N
O
O
35XDT
36 (1.5%)
Synthetic diverse- DOS
3P6AH
27 (1.1%)
N
O
VV0YX
18 (1.2%)
N09V9
17 (1.1%)
O
O
O
N
Commercial
O
N
N
N
O
N
N
RYLFV
197 (3.0%)
C143P
186 (2.8%)
R5W4K
142 (2.1%)
RYLFV
242 (4.7%)
91DYR
48 (0.8%)
PA9KP
45 (0.7%)
N
N
O
O
S
7Y2BB
34 (0.6%)
RYZ2V
33 (0.5%)
8SHWK
80 (1.2%)
21963
109 (1.6%)
FIGURE 10.5
Most frequent scaffolds (cyclic systems or molecular frameworks) found in
1490 approved drugs, a collection of 2472 natural products, 6623 synthetic diverse compounds
obtained from academic groups using techniques such as DOS, and 6152 compounds from a
commercial vendor library. The three last data sets were obtained from the work reported by
Clemons et al. [85]. The frequency and percentage are displayed.
