Prediction of hERG Channel Inhibition Using In Silico Techniques - Ion Channels and Their Inhibitors - page 195

feature responsible for the polyspecificity of the hERG channel, mainly due to the
possibility to make multiple and compound specific interactions. In the closed
conformation, the S6 domains intersect at the cytoplasmatic side of the channel,
closing the inner pore and preventing the flow of K þ ions. During channel activa-
tion, the S6 domains rotate outward, opening the inner pore and allowing ions to
flow.
The hERG channel and other K + -channels contain a PAS domain on the cyto-
plasmic N-terminus, [ 23 ] which is involved in protein-protein interactions.
Although the function of the PAS domain in the hERG channel is not understood,
mutagenesis studies show that disruption of this domain reduces the outward
current and prolongs the QT interval [ 24 ].
Also, the role of the C terminus domain is not yet completely clarified, although
a cAMP-binding domain is located there. cAMP accelerates the deactivation
kinetics of the hERG channel [ 25 ].
4 Ligand-Based Approaches
4.1 Pharmacophore Models
Several pharmacophore models have been published up to date. They provide
a powerful tool for the identification of potential hERG blockers by virtual screen-
ing of compound databases. Some pharmacophore models were already reviewed
elsewhere [ 26 , 27 ].
Morgan and Sullivan [ 28 ] analyzed a set of class III antiarrhythmic drugs. In the
pharmacophore model, the charged nitrogen is linked by 1-3 atoms to two features,
which might be an aromatic ring or an alkyl moiety. A third feature, consisting of
a para-substituted ring, is linked with the charged nitrogen through a chain of 1-4
atoms. The model derived by Ekins et al. [ 29 ] was generated from a training set of
15 compounds taken from the literature. The pharmacophore model contains one
positive ionizable feature connected with four hydrophobic moieties. A “construc-
tionist approach” was used by Cavalli et al. [ 30 ] to develop a pharmacophore
model. The crystal structure of astemizole was used as template on which
molecules with similar geometry were aligned, leading to the addition of new
pharmacophoric features, which were not present in the previous pharmacophore.
To the initial pharmacophore consisting of a basic nitrogen (N) and two aromatic
features (C0 and C1), a fourth feature defined by the aromatic ring (C2) of an
astemizole derivative was added. Thus, the charged nitrogen group (N) is connected
to three aromatic groups (C0-C2). The authors noted that all the hERG blockers
tested have the C0 feature, while some molecules lack the C1 or C2 moieties. They
also found that a polarizable function in C0, such as a carboxylic or a sulfonamidic
group, may also influence the activity.