Prediction of hERG Channel Inhibition Using In Silico Techniques - Ion Channels and Their Inhibitors - page 229

5.11 Orthogonal Binding Site?

In contrast to the accepted idea that the blockers bind the hERG channel longitudi-
nally to the z axis, Zachariae et al. [ 118 ] proposed an orthogonal binding site.
During MD simulations of a homology model of the hERG channel in the closed
state the four Tyr652 adopted a “down conformation” with the aromatic ring plane
pointing into the central cavity. The “down conformation,” which is stabilized by
the interactions with Phe656, opens a way to the membrane. This can explain why
the cavity size of hERG in the closed state is larger than the vestibule of KcsA
and can accommodate bulky compounds, such as MK-499 [ 3 ]. Docking studies
performed on several compounds such as dofetilide, terfenadine, and cisapride, and
previously published pharmacophore models [ 28 - 30 , 33 ] corroborate this model.
The pose of dofetilide suggests that the charged nitrogen atom is close to the K þ
binding site, and that the two aromatic rings form

p

-stacking interactions with two
Tyr652 of opposite subunits. The binding position of terfenadine shows that the two
neighboring aromatic rings of the molecule interact with two Tyr652 of adjacent
subunits. In the case of cisapride, the two phenyl rings interact with two opposite
Tyr652.

5.12 Docking Results

The main goal of the docking technique is to model the molecules in the binding site
and to find the bound conformation of the compounds as close as possible to the
crystal poses, allowing the analysis of the interactions between the ligand and
the target protein.
Mitcheson et al. [ 6 ] docked MK-499 into a closed state homology model of the
hERG channel. The analysis of the poses shows that the p-CN phenyl ring and
the benzopyran form

p

-stacking interactions with Phe656 and Tyr652, while the
methanesulfonanilide moiety is placed into the pocket delimited by Gly648, Thr623
and Ser624.
Karczewski et al. [ 104 ] docked MK-499 into a homology model of the hERG
channel in the closed state. The docking poses of MK-499 predict that the hydroxyl
group forms a hydrogen-bond with Ser624, but the contribution of this interaction
to the complex stabilization is modest due to the distance between the two hydroxy
oxygens (3.4 ˚ ). In the docking pose of the carbonyl analog the distance between
the oxygen of the side chain of Ser624 and the one of the substituent is 3.0 ˚ .This
indicates that the hydrogen-bond between the carbonyl analog and Ser624 is
stronger than the previously discussed one, which might explain the insensitivity
to the Phe656Ala mutation.
Two possible binding modes of chloroquine were proposed by Sanchez-Chapula
et al. [ 5 ]. In the first binding mode, the molecule forms -stacking interactions with

Phe656 on three subunits, as well as a hydrogen-bond with Ser649, while the

p