Prediction of hERG Channel Inhibition Using In Silico Techniques - Ion Channels and Their Inhibitors - page 227

5.10 Case Studies: Docking Studies and Improvement
of the Selectivity

A structure-activity relationship combined with docking studies was used by Price
et al. [ 115 ] to reduce the hERG affinity in a series of CCR5 antagonists. Docking
of the lead compound into a homology model of the hERG channel in the closed
state revealed that the benzimidazole group fits perfectly to the lipophilc region
described by the four Tyr652. This result suggested that it was possible to reduce
the affinity of the compounds for the hERG channel by replacing the benzimidazole
moiety with other moieties. This led to the discovery of maraviroc, a potent CCR5
antagonist, which does not interact with the hERG channel.
Micheli et al. [ 100 ] performed an interesting study on the combination of
docking experiments with structure-activity relationship (SAR) to improve the
affinity of a series of 1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines with
the dopaminergic receptor D 3 and to avoid the interaction with the hERG channel.
The compounds were docked manually into homology models of the hERG channel
in the closed and the open state. The docking experiments predict that the lead
compound assumes a U-conformation, probably due to interactions with Tyr652,
Phe656 and intramolecular -stacking interaction. The pose shows that the charged

nitrogen atom and the quinoxaline ring form hydrogen-bonds with serines in the
pore of the hERG channel. Based on the docking results, two strategies were used to
tackle hERG liability. In the first one the hydrophilicity of the compounds was
increased. This strategy led to a compound highly selective for the D 3 receptor and
with a reduced affinity for the hERG channel. The second strategy was to reduce the
p

p

interactions between the isoxazolyl group and the hERG channel breaking
the coplanarity between the isoxazolyl and the benzazepine moieties. This strategy
led to a reduction of hERG activity, without affecting the D 3 potency.
Also, Dinges et al. [ 116 ] used a combination of SAR and docking results to
develop KDR kinase inhibitors with an optimized hERG profile. One kinase
inhibitor was manually docked into a model of the hERG channel in the closed
state. The best fit was obtained by orienting the compound parallel to the pore of the
channel, with the acetylenic ether group oriented toward the cytoplasmatic side of
the hERG channel. The pose predicts that the 1,4-dihydroindeno [1,2- c ]pyrazole
forms

-stacking interactions with Phe656, that the charged nitrogen atom on the
N -methylpiperazine moiety can make

p

-cation interactions with Tyr652, and that
the external nitrogen forms a hydrogen-bond with Ser624. Based on this pose three
strategies were developed. The first strategy consisted on the modification of the
basic side chain. This approach led to compounds with a reduced hERG affinity, but
the antitumoral efficacy was compromised. In the second strategy the polarity of
the acetylenic chain was increased. This led to molecules with an attenuated
hERG activity, but also the KDR affinity was reduced, except for the compound
bearing the glycol ether moiety that inhibited 76% tumor growth in the MX-1
tumor xenograft model. The third approach used the introduction of groups
that disrupt electronically or sterically the

p

p -stacking interaction between the