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Abstract:
Two voltage-dependent potassium channels, Kv1.1 (KCNA1)
and Kv1.2 (KCNA2), are found to co-localize at the juxtaparano-
dal region of axons throughout the nervous system and are
known to co-assemble in heteromultimeric channels, most
likely in the form of the concatemer Kv1.1–1.2
(3)
. Loss of the
myelin sheath, as is observed in multiple sclerosis, uncovers
the juxtaparanodal region of nodes of Ranvier in myelinated
axons leading to potassium conductance, resulting in loss of
nerve conduction. The selective blocking of these Kv channels
is therefore a promising approach to restore nerve conduction
and function. In the present study, we searched for novel in-
hibitors of Kv1.1–1.2
(3)
by combining a virtual screening proto-
col and electrophysiological measurements on a concatemer
Kv1.1–1.2
(3)
stably expressed in Chinese hamster ovary K1
(CHO-K1) cells. The combined use of four popular virtual
screening approaches (eHiTS, FlexX, Glide, and Autodock-Vina)
led to the identification of several compounds as potential in-
hibitors of the Kv1.1–1.2
(3)
channel. From 89 electrophysiologi-
cally evaluated compounds, 14 novel compounds were found
to inhibit the current carried by Kv1.1–1.2
(3)
channels by more
than 80% at 10
m
m
. Accordingly, the IC
50
values calculated
from concentration–response curve titrations ranged from 0.6
to 6
m
m
. Two of these compounds exhibited at least 30-fold
higher potency in inhibition of Kv1.1–1.2
(3)
than they showed
in inhibition of a set of cardiac ion channels (hERG, Nav1.5,
and Cav1.2), resulting in a profile of selectivity and cardiac
safety. The results presented herein provide a promising basis
for the development of novel selective ion channel inhibitors,
with a dramatically lower demand in terms of experimental
time, effort, and cost than a sole high-throughput screening
approach of large compound libraries.
