Biomedical Engineering Reference
In-Depth Information
bulky substituents in
para
position prevent to adopt the conformations of clofilium
and its nitro analog. The pose of clofilium predicts that the chlorine atom forms
hydrogen-bond interactions with Ser624. In the proposed binding conformation of
ibutilide, the
para
-substituent interacts with Thr623, Ser624, and the phenyl ring
forms
-stacking interaction with Tyr652. The amide analog cannot adopt the
binding mode of ibutilide and interacts with Thr623 and Ser624, probably due to
the lack of the sulfonyl and of the hydroxyl groups. The interactions with Tyr652
are weak, and this explains the low affinity of the amide analog for the hERG
channel. In all four compounds, the tail makes hydrophobic interactions with
Phe656.
p
5.8 Two or Three Binding Interactions?
Mutagenesis studies of the S6 domain identified Tyr652 and Phe656 as important
sites of interaction. These results led to propose that the charged nitrogen atom may
form
-cation interactions with Tyr652 or Phe656, and that the aromatic moieties
of the blockers can make
p
-stacking interactions with the amino acids cited above.
Choe et al. [
97
] suggested a model with three key interactions: hydrogen-bond
interaction between the protonated nitrogen atom and the carbonyl oxygen of
Thr623;
p
-stacking interactions between an aromatic ring and Tyr652; hydropho-
bic interaction between an hydrophobic moiety of the blocker and Phe656. To test
the three key interactions model, 69 known hERG blockers were divided into eight
binding types and further subdivided into two groups based on the number of
interactions with the hERG channel (two or three) predicted by the model. Consis-
tent with the three key interactions model, the different distribution of pIC
50
values
between the two groups reveals that the blockers can form three interactions, and
that the compounds, which are predicted to form more interactions show a higher
mean pIC
50
value.
p
5.9 Docking Studies and Prediction of hERG Binding Affinity
Rajamani et al. [
89
] developed a two-state binding affinity model to predict the IC
50
values of potential hERG blockers. Homology models of the hERG channel in the
closed and open states were constructed using as template the crystal structures of
KcsA and MthK, respectively. Initially, the S6 helix of the reference closed-state
model was rotated to match MthK S6 helix, and subsequently the channel was
closed rotating the S6 helix by 1
. The partial open-state model (10
translation
away from the reference model) and the fully open state (19
translation away from
the reference model) were used to dock 32 hERG inhibitors. The best pose for each
ligand was then minimized within the channel, and finally the minimized pose
