Biomedical Engineering Reference
In-Depth Information
Ser624, and the charged nitrogen atom of the piperidine ring forms a
-cation
interaction with Phe656. The
p
-methoxybenzene ring is shown to be exposed to the
cytoplasm.
The pose of terfenadine reported by Du et al. [
92
] shows that the
t
-butylphenyl
moiety forms hydrophobic interactions with the amino acids Ser649, Tyr652,
Ala653, and Phe656, whereas the diphenylmethanol group makes hydrophobic
interactions with Ser624, Ser649 and Tyr652. The phenyl ring of the hERG blocker
ibutilide is predicted to form hydrophobic interactions with Thr623, whereas the
alkyl chain makes hydrophobic interactions with Thr623, Ser649, Tyr652, Ala653
and Phe656. Furthermore, the nitrogen atom of the methylsulfonamide moiety can
form a hydrogen-bond with Thr623.
Singleton et al. [
93
] docked a series of dofetilide derivatives bearing a fluores-
cent group into a hERG channel homology model of the closed state. The poses
highlight that the compounds lie in the inner pore, where they interact with Tyr652
and Phe656. The polycyclic conjugated dyes occupy the central cavity.
Models of hERG channel in the open and closed state were generated by
Stansfeld et al. [
94
] using as template the structure of MthK, KvaP, and KcsA.
As the models showed only partial agreement with mutagenesis data, a series of
KcsA-based intermediate models were generated rotating the four S6 domains. To
obtain homology models where the Phe656 can interact with the blockers also a
series of intermediate models, which simulate the channel opening, were created.
The docking poses of compounds E-4031, dofetilide, ibutilide, and dronedarone
show that the methanesulphonamide makes hydrogen-bonds with Thr623 and
Ser624. A phenyl ring is predicted to form
p
-stacking interactions with Tyr652.
The methanesulphonamide MK-499 does not interact with the amino acids Thr623
and Ser624. The pose of dronedarone predicts that the charged nitrogen atom is
placed in the same position of the K
รพ
identified in the inner pore in the KvaP crystal
structure. The docking pose of fluvoxamine suggests that the protonated nitrogen is
placed below Phe656, whereas the trifluoromethyl group lies in the central cavity
and shows hydrogen-bond interactions with Thr623 and Ser624. The poses of
propafenone and vesnarione make
p
-stacking interactions with Tyr652. For
propafenone, it is also predicted that the charged nitrogen atom is placed between
the Phe656 residues, with which it can form
p
-cation interactions. The pose of
terfenadine indicates that this compound interacts with Tyr652 and Phe656. In the
case of clofilium and cisapride the molecules make
p
-stacking interactions with
Tyr652, whereas the polar groups interact with the amino acids Thr623 and Ser624.
In the docking poses of quinidine and chloroquine, the basic nitrogen is placed
above Phe656 and the ring system forms
p
-stacking interactions with Tyr652.
In summary, numerous docking studies have been conducted and they support
findings from QSAR and mutation studies. However, with respect to prediction
of strong hERG binders, docking definitely suffers from the still unsolved issue of
proper binding free energy calculations. In addition, the channel is quite flexible
and compounds might bind to the closed, semiopen and/or open states. This renders
hERG binding prediction solely based on docking quite risky.
p
