Biomedical Engineering Reference
In-Depth Information
opposite subunits but not with Ser624. Based on the results of the inhibition curves,
the three compounds were docked into homology models of the hERG channel in
the open state. The docking pose of cisapride shows
p
-
p
interaction between one
aromatic ring of the molecule and Tyr652, and CH-
interaction between the
Tyr652 of adjacent subunits and the methylene group near the protonated nitrogen
in the piperidine ring. The second aromatic ring of the molecule forms
p
-stacking
interactions with Phe656, and the carbonyl oxygen interacts via hydrogen bond
with Ser624. The docking pose of E-4031 indicates that the aromatic rings form
p
p
interactions with herringbone geometry with two Tyr652 of adjacent subunits,
that the pyridine ring makes a hydrogen-bond with Ser624, and that the methyl
group in the methansulfonamide moiety forms a CH-
p
interaction with the amino
acid Phe656. The pose of terfenadine shows that the two terminal aromatic rings
and the second benzene ring of the benzhydryl moiety interact with Tyr652 and
Phe656 through
-
p
interaction with herringbone geometry. Based on these
interactions, the introduction of an electron withdrawing group, or the introduction
of a bulky substituent, which disrupts the interactions with Tyr652 and Phe656, can
lead to a terfenadine derivative with an attenuated hERG binding affinity. The
docking poses of cisapride, E-4031 and terfenadine proposed in this study, in
contrast to a previous study [
103
], highlighted that
p
-
p
p
-cation interactions might
not always play a dominant role, and that
p
-
p
interactions with herringbone
geometry and CH-
p
interactions could be important in the hERG-blocker complex
formation.
5.7
Influence of Para-Substituents on the Phenyl Ring
Mutagenesis data and docking studies suggest that the
para
-substituent of phenyl
rings in inhibitors forms polar interactions with Thr623 and Ser624[
12
]. To test this
hypothesis, a structure activity relationship of ibutilide derivatives was performed
to analyze the influence on the IC
50
of different
para
-substituents [
105
]. The IC
50
of
ibutilide analogs measured on wild-type hERG channels showed a rank order
of nitro
amide. Similar results were obtained also with
dofetilide derivatives. These results are in agreement with the 3D-CoMSiA and
the 3D-pharmacophore models developed by Cavalli et al. [
30
], which indicated the
importance of a polar or a polarizable region close to an aromatic ring. All these
information suggest that it is possible to reduce the hERG potency by modifying the
nature of the substituent in the
para
position of phenyl rings and thereby develop
compounds with a better toxicological profile.
The docking poses of clofilium and the nitro analog show that the
para
-substituent
interacts with Thr623 and Ser624 and that the phenyl ring forms
chlorine
amine
>
>
>
-stacking
interaction with Tyr652. The ethyl group attached to the protonated nitrogen,
which is placed in the center of the central cavity, forms hydrophobic interactions
with Tyr652. The second ethyl group present in some docked inhibitors may form
hydrophobic interactions with a second Tyr652. The docking poses indicate that
p
