Prediction of hERG Channel Inhibition Using In Silico Techniques - Ion Channels and Their Inhibitors - page 230

diethyl groups of the tail of the molecule form hydrophobic interactions with
Tyr652. In the second binding pose, -stacking

interactions with Tyr652 and Phe656. The nitrogen atom attached to the quinoline
forms a hydrogen-bond with Ser649 and the ethyl group attached to the charged
nitrogen interacts with Tyr652 through hydrophobic interactions.
The aligned inhibitors used to generate the CoMSiA model of Pearlstein et al.
[ 21 ] were docked into a homology model of the hERG channel in the open state.
The proposed binding mode suggests that the Phe656 forms

the quinoline group makes p

p

-stacking interactions
with an aromatic ring, that a second hydrophobic group can interact with another
Phe656, and that the charged nitrogen atom makes

-cation interactions with
Tyr652. The tail region of the blockers reaches into the pore region that extends
from Tyr652 to the selectivity filter.
Moreno et al. [ 4 ] studied the effect of irbesartan on hERG, KvLQT1 + minK,
hKv1.5 and Kv4.3 channels using the patch clamp technique. The homology
models of hERG and hKv1.5 channels in the closed state were generated using
the KcsA crystal structure as template. The pose obtained from manual docking of
ibersartan shows that

p

the blocker forms a hydrogen-bond and p -stacking

interactions with Tyr652, p -stacking interactions with Phe656 and van der Waals

interactions with Thr623.
The pose of clofilium proposed by Perry et al. -stacking

interactions between the Tyr652 and the phenyl ring of the molecule, in addition
to the hydrophobic interactions of the aliphatic tail of clofilium with Phe656 and the
interactions of the chlorine with Thr623, Ser624, and Val625.
Duncan et al. [ 88 ] docked erythromycin into a model of the hERG channel in the
open state. All the poses with low energy interact with Phe656, while the interaction
with Tyr652 is prevented by the large size of the molecule that restricts the ability of
erythromycin to move up into the inner cavity. The docking poses obtained with a
model of the closed state shows high energy values due to steric clashes, indicating
that the molecule cannot fit into the closed-state channel. Visual inspection reveals
that the molecule is too large for the central cavity of the hERG channel in the
closed state.
Yoshida et al. [ 49 ] docked the hERG blocker pimozide into an open-state model
to examine the correspondence between the molecular determinants derived from
the 2D-QSAR model with the 3D structure of the channel. The docking pose
suggests that the fluorine atoms and the carbonyl group of pimozide forms hydro-
gen bond interactions with Ser649 and Ser624, respectively.
Hosaka et al. [ 95 ] performed a flexible docking of nifekalant into an open-state
model. Consistent with the mutagenesis data, docking simulations suggest that
the entire molecule is placed in the central cavity surrounded by Thr623, Ser624,
Tyr652, and Phe656 of different subunits and located in close vicinity to Ser649.
¨ sterberg et al. [ 98 ] docked a series of sertindole analogs into a homology model
of the hERG channel in the open state. The docking pose of sertindole suggests that
the carbonyl oxygen forms a hydrogen bond with the water molecule located in the
selectivity filter. The imidazolidinone group makes good interactions with Thr623

[ 12 ] shows p