Biomedical Engineering Reference
In-Depth Information
Pearlstein et al. [
21
] developed a “drain plug” model through a combination of
hERG homology modeling and the CoMSIA analysis of 22 sertindole derivatives
and 10 structurally diverse hERG inhibitors. The analysis of the hERG homology
model reveals a “drain plug” picture, which is complementary to the shape of the
cavity, where the amino acids responsible for the interactions are located. The
“drain plug” pharmacophore model consists of two aromatic groups that can
interact with Phe656, and a basic nitrogen that might interact with Tyr652. They
also suggest that a hydrophobic or an aromatic substituent in this portion of the
molecule might improve the potency of hERG blockers through the interaction with
Tyr652.
Aronov et al. [
31
] used a set of 85 hERG blockers to develop three hypotheses of
three-point pharmacophores. The first two hypotheses are in agreement with the
C0-N-C2 and C0-N-C1 pharmacophores published by Cavalli et al. [
30
]. In the
third pharmacophore model, there is a hydrogen bond acceptor feature placed
between the charged nitrogen and the aromatic ring, at a distance of 1.8-3.7
˚
from the latter one. Similarly, Testai et al. [
32
] found that an acceptor feature is
normally placed within 4-6
˚
from an ionizable center.
Aronov et al. [
33
] also used the pharmacophore elucidation module implemented
in MOE to analyze an in-house dataset of 194 uncharged compounds. At the
beginning, two-point queries are generated and used to make more complex
n
-point queries through a “build up” method. Two five-point pharmacophore models
containing three hydrophobic/aromatic features and two hydrogen bond acceptors
were selected from all generated pharmacophore models. These two five-point
pharmacophore models, which differ only in the position of one of the hydrogen
bond acceptors, were merged into a six-point pharmacophore. The two five-point
pharmacophores were able to correctly classify 78% and 69% of potent hERG
blockers of the dataset. The six-point pharmacophore matched 21% (IC
50
<
10
m
M)
m
and 44% (IC
50
<
30
M) of hERG blockers and 4% of nonblockers. Applying a
ClogP
1 cutoff, the number of false-positives was reduced in all three models.
Crumb et al. [
34
] developed a qualitative pharmacophore model through the
analysis of 11 antipsychotic drugs. The model, which consists of one aromatic
query surrounded by three hydrophobic moieties, is matched by the most potent
hERG blockers present in the dataset.
A collection of 1,075 hERG inhibitors was used by Johnson et al. [
35
] to develop
a series of pharmacophore and QSAR models. As seen in previous studies, the basic
nitrogen, which is placed 6-9
˚
apart from a centroid of an aromatic ring, was
found to be an important feature for hERG blockers. In the second pharmacophore
model, the effect on the activity of the basic nitrogen is attenuated by the presence
of two hydrogen bond acceptors and a lipophilic group. This might be a useful hint
for development of compounds without reduced hERG blocking activity. In the
third pharmacophore, the aromatic rings are placed at the opposite side of the
molecule and are separated by 14 bonds. In the fourth model, the aromatic ring
feature is coupled with a hydrogen bond moiety. The fifth pharmacophore model
consists of two aromatic rings placed within 6-13
˚
>
from two hydrogen bond
donors.
