Biomedical Engineering Reference
In-Depth Information
and Ser624. Interestingly, the charged nitrogen is almost superposed to the crystal-
lographic position of the K
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ion in KvaP.
Farid et al. [
99
] used the induce-fit docking protocol to dock 12 known hERG
blockers into hERG channel models in the open and closed state. S-terfenadine
interacts with four Tyr652 and two Phe656. It forms T-shaped interactions with four
of the six aromatic amino acids. The docking results show that the poses of R- and
S-terfenadine are similar. S-terfenadine interacts simultaneously with four Tyr652
and two Phe656. The replacement of a T-shape interaction with a parallel one is the
only important difference between the S-and R-terfenadine. S-terfenadine forms
hydrogen-bonds with the backbone oxygen of the amino acid Leu622, and with the
side chains of Ser624 and Ser649. R-terfenadine makes four hydrogen-bonds, three
of them are with Ser624 of different subunits and the fourth one is with Tyr652.
Also,
)-cisapride are similar. (+)-cisapride
interacts with three Tyr652 and two Phe656, making two T-shaped interactions
with the Tyr652 on opposite subunits, and a parallel interaction with one Phe656.
The pose predicts also that the piperidine NH forms a hydrogen-bond with Ser624.
The only difference between (+)-cisapride and (
the poses of (+)-cisapride and (
)-cisapride is that the interaction
with Phe656 is replaced by an interaction with Tyr652. MK-499 interacts simulta-
neously with four aromatic amino acids (two Tyr652 and two Phe656). The
molecule is predicted to be near Thr623, Ser624, Ser649, and Ala653, with which
it can interact. The aliphatic chain of S-ibutilide interacts with three Tyr652 and
one Phe656. The phenyl ring forms a T-shaped interaction with Tyr652. The
methanesulfonanilide group and the basic nitrogen are predicted to make hydro-
gen-bonds with two Ser624 of adjacent subunits. The pose of R-ibutilide is a
mirror image of the one of S-ibutilide. Clofilium makes simultaneous interactions
with four Tyr652 and three Phe656. The pose predicts one T-shaped interaction with
Tyr652 and two with Phe656. Sertindole interacts with three Tyr652, two of which
make T-shaped interactions. The docking pose shows also interactions with one
Phe656. The pose of sertindole A5 predicts the interactions with two Tyr652 and
one Phe656. It makes T-shaped interactions with one Tyr652 and one Phe656. The
pose predicts also a hydrogen-bond between the backbone oxygen of Thr623 and
the dimethylamine NH group. Sertindole A1-A4 interact with Tyr652 and Phe 656.
Moreover, it makes hydrogen-bonds with Ser649 and with the backbone oxygen of
Leu622.
Masetti et al. [
91
] constructed a homology model of the hERG channel in the
open and in the closed state. Subsequently, the two models were embedded in a
membrane bilayer, solvated, and the system was neutralized. Both models were
subjected to molecular dynamics simulations of 5 ns. The docking of astemizole
into the hERG channel in the closed state could not provide any reasonable pose.
Reliable binding poses were identified only when astemizole was docked into
snapshots of MD simulations of the hERG channel in the open state. The top
ranked pose shows that the benzimidazole ring forms
-stacking interactions
with Tyr652 and parallel displaced interactions with Phe656 of the same subunit.
The
p
-fluorophenyl interacts with Tyr652 through parallel displaced interactions.
The pose predicts also a possible hydrogen-bond between the fluorine atom and
p
