Biomedical Engineering Reference
In-Depth Information
literature were corrected as previously described. The analysis of the contribution
of the descriptors revealed the positive contribution of the E-state key of the
aromatic carbon and of the nitrogen atom with a free lone pair. In particular, the
model indicates that a separation of 9-10 bonds between two phenyl rings increases
hERG affinity. This is consistent with previously published pharmacophore models,
which indicates the importance of the presence of a tertiary amine linked with two
aromatic rings. The final model achieved the mean absolute errors of 0.62 and
0.62 for the training set (189 compounds) and test set (41 compounds). Different
from other publications, the authors used the mean absolute errors as performance
measure, which makes it complicated to compare their model with the results
already published.
The 1D-, 2D-, and 3D- QSAR models discussed highlight the importance of the
basic nitrogen and of the hydrophobic and aromatic groups for strong hERG
blockers. To reduce hERG affinity, the QSAR models suggest to reduce the number
of aromatic rings, to modulate the pKa of the basic nitrogen, and to reduce the
lipophilicity of the molecule. It is noteworthy that the compounds with a carboxylic
group are unlikely to be hERG blockers.
4.5 Classification Models
To discover potential hERG blockers classification techniques became an important
and powerful tool. Although they do not need accurate IC
50
values, it is necessary to
set up a threshold, which defines if the compounds are considered as active or as
inactive.
Bains et al. [
59
] chose an IC
50
of 1
M as threshold to define hERG blockers and
nonblockers. Tobita et al. [
60
] used thresholds of 1
m
M to classify active
and inactive compounds. Roche et al. [
61
], Dubus et al. [
62
], Ekins et al. [
51
], Thai
et al. [
63
-
65
], and Chekmarev et al. [
66
] classified the hERG blockers into three
different classes: low IC
50
(lower than
m
M and 40
m
1
m
M, blockers), medium IC
50
(between 1
<
and 10
m
M), and high IC
50
(higher than
10
m
M, nonblockers). Doddareddy et al.
>
[
67
] used the cutoff values of IC
50
<
3
m
M, 6
m
M and 10
m
M to define hERG
inhibitors, and of
30
m
M for the hERG inactives. O'Brien et al. [
68
] selected the
>
value of 20
M to define hERG inhibitors. Sun et al. [
69
] and Jia et al. [
70
] defined a
compound as hERG blocker if it has an IC
50
value lower than 30
m
M. Buyck et al.
[
71
] used the threshold of 130 nM to define if the compounds are hERG blockers or
not. Catana et al. [
72
] used an IC
50
of 40
m
M as a cutoff to define the separation
between hERG blockers and nonblockers. Li et al. [
41
] used the threshold values of
1
m
m
M, 5
m
M, 10
m
M, 20
m
M, 30
m
M, and 40
m
M. Some approved drugs have an IC
50
value between 1 and 10
m
M. Typically, a drug is considered safe if the IC
50
value is
higher than 10
M[
53
]. To assess the safety of compounds also the ration between
the free therapeutic plasma concentration and the hERG IC
50
has to be considered.
Generally, a molecule with a margin greater than 30-fold between the free thera-
peutic plasma concentration and the hERG IC
50
is regarded as safe [
73
].
m
