Biomedical Engineering Reference
In-Depth Information
Thr623 makes hydrogen-bonds with the hydroxy group and the protonated nitrogen
atom, and that Ser624 forms hydrogen-bonds with the hydroxy moiety. The pose of
propafenone docked into the homology model of the hERG channel in the open
state shows
-stacking interactions between the phenyl ring and Tyr652, and that
the hydroxyl and the carbonyl group as well as the ether oxygen form hydrogen-
bonds with Thr623 and two Ser624 of adjacent subunits, respectively. The docking
pose of propafenone into the hERG channel in the open state shows that the
protonated nitrogen moves in the direction of the cytoplasm. This indicates
that the propafenone moves upward when the hERG channel closes. The other
trapped compound, the piperidine analogue, shows a similar poses. The poses of
nontrapped propafenone derivatives bearing a 2,3-dimethylphenyl-1-piperazinyl
ring docked into the hERG open state, predict that the carbonyl group and the
ether oxygen form two hydrogen-bonds with Ser624 of different subunits. The
conformation of the nontrapped compounds is similar to the pose of propafenone,
with the substituent located into the inner pore. The nontrapped 1-[4-{3-[4-
(2,3-dimethylphenyl)piperazin-1-yl]-2-hydroxypropoxy}-phenyl]ethanone makes
a
p
-cation interactions with Phe656, and a hydrogen-bond with Ser624. Like the
other nontrapped molecule, the 2,3-dimethylphenyl ring is placed in the inner pore.
Even if the compound has a smaller volume than propafenone due to the lack of the
second phenyl ring, the molecule is not trapped. These poses indicate that electro-
static interactions are important for drug trapping, because the protonated nitrogen
is pushed up during the channel gating. Witchel et al. [
11
] indicated that the amino
acid Phe656 plays an important role in the interaction with propafenone, while the
mutations of other amino acids to alanine do not affect the hERG block. In this
study, the results suggest that also the amino acids Thr623 and Ser624 might
interact with propafenone. The main structural difference between trapped and
nontrapped compounds is the bulkiness of the substituent attached to the protonated
nitrogen atom, which is larger in the nontrapped ones. In light of this consideration,
the authors suggest that the size of the substituent might be one of the contributing
factors playing a role in the drug trapping/nontrapping. In detail, all these results
indicate that the compounds that are small enough and that can alter the conforma-
tion can be trapped, in contrast to compounds with a bulky substituent that can
prevent the closure of the activation gate with a “foot-in-the-door” like mechanism.
p
5.3 Amino Acids Involved in hERG Inhibition
At the base of the hERG channel, two concentric rings formed by four Tyr652 and
four Phe656 are located. The ring formed by the four Phe656 is placed near the
cytoplasm, whereas the ring made by four Tyr652 face the central cavity. These two
rings can make hydrophobic,
p
-stacking and
p
-cation interactions, explaining the
polyspecificity of the hERG channel.
Several authors studied the physicochemical properties responsible for interac-
tions with Tyr652 and Phe656 with the ligands. Fernandez et al. [
103
] studied the
