The hERG potassium channel and drug trapping: Insight from docking studies with propafenone derivatives

Article abstract of DOI:10.1002/cmdc.200900374

The inner cavity of the hERG potassium ion channel can accommodate large, structurally diverse compounds that can be trapped in the channel by closure of the activation gate. A small set of propafenone derivatives was synthesized, and both use-dependency and recovery from block were tested in order to gain insight into the behavior of these compounds with respect to trapping and non-trapping. Ligand-protein docking into homology models of the closed and open state of the hERG channel provides the first evidence for the molecular basis of drug trapping.

Full text of DOI:10.1002/cmdc.200900374

MED
DOI: 10.1002/cmdc.200900374
The hERG Potassium Channel and Drug Trapping: Insight
from Docking Studies with Propafenone Derivatives
Khac-Minh Thai,[a, c] Andreas Windisch,[b] Daniela Stork,[b] Anna Weinzinger,[b]
Andrea Schiesaro,[a] Robert H. Guy,[d] Eugen N. Timin,[b] Steffen Hering,[b] and
Gerhard F. Ecker*[a]
The inner cavity of the hERG potassium ion channel can ac-
commodate large, structurally diverse compounds that can be
trapped in the channel by closure of the activation gate. A
small set of propafenone derivatives was synthesized, and
both use-dependency and recovery from block were tested in
order to gain insight into the behavior of these compounds
with respect to trapping and non-trapping. Ligand–protein
docking into homology models of the closed and open state
of the hERG channel provides the first evidence for the molec-
ular basis of drug trapping.
Introduction
Acquired long QT syndrome causes severe cardiac side effects
and is a significant problem in clinical studies of drug candi-
dates.[1–3] One of the causes behind the development of ar-
rhythmias related to long QT syndrome is inhibition of the
human ether-ꢀ-go-go-related gene (hERG) potassium chan-
nel.[4–6] Hence there is increasing interest in computational
models that can predict affinity for hERG binding in the early
phases of drug discovery and development.[7–12] The inner
cavity of the hERG channel is composed of a promiscuous
binding site and is capable of trapping diverse compounds in
the closed-channel state.[13–18]
amiodarone, cisapride, droperidol, and haloperidol do dissoci-
ate. All eight compounds dissociated from the open channels.
In this study, a small set of propafenone derivatives were
synthesized and tested for hERG activity. Docking into protein
homology models of the open and closed states of the hERG
channel provide the first insight into the structural basis of
trapping phenomena.
Results and Discussion
The majority of drugs interact with hERG within the central
cavity of the channel, thus blocking K+ ion conduction. Based
on the data from alanine scanning and site-directed mutagen-
esis experiments, the drug binding site seems to involve three
residues at the base of the selectivity filter (Thr623, Ser624,
and Val625) and four on the S6 transmembrane helix (Gly648,
Tyr652, Phe656 and Val659). In the tetrameric channel protein,
two concentric rings formed by the symmetric tetrad of
Phe656 groups located closer to the mouth of the channel,
and by the four Tyr652 residues situated closer to the pore
helix, thereby facing the interior of the conduction pathway,
contribute to multiple and compound-specific interactions. In
contrast to other potassium channels, the inner cavity of the
hERG K+ ion channel is sufficiently large to physically accom-
modate structurally diverse compounds that can be trapped in
the channel upon closure of the activation gate.[17,18] This phe-
nomenon of drug trapping was observed from many high-
and low-affinity compounds, which only recover from the
block relatively slowly.[14–18,19]
Chemistry of propafenone and its derivatives
The preparation of the tertiary amines (Table 1) was carried out
analogously to the synthesis of propafenone (Scheme 1).[20]
Thus, an appropriate o-hydroxyphenone 1 was allowed to
react with epichlorohydrine to give the epoxides 2. Subse-
quent treatment with an amine yielded the corresponding
propanolamines 3, which were converted into their respective
[a] Dr. K.-M. Thai, A. Schiesaro, Prof. Dr. G. F. Ecker
University of Vienna, Department of Medicinal Chemistry
Emerging Field Pharmacoinformatics
Althanstrasse 14, 1090 Wien (Austria)
Fax: (+43)1-4277-9551
E-mail: gerhard.f.ecker@univie.ac.at
[b] A. Windisch, Dr. D. Stork, Dr. A. Weinzinger, Prof. Dr. E. N. Timin,
Prof. Dr. S. Hering
University of Vienna, Department of Pharmacology and Toxicology
Althanstrasse 14, 1090 Wien (Austria)
[c] Dr. K.-M. Thai
University of Medicine and Pharmacy at Ho Chi Minh City
Faculty of Pharmacy, Department of Pharmaceutical Chemistry
41 Dinh Tien Hoang St., Dist. 1, Ho Chi Minh City (Vietnam)
We recently investigated the kinetics of hERG channel inhibi-
tion and recovery from block by eight blockers at different fre-
quencies.[15] The results indicated that apparently ’trapped’
drugs (bepridil, domperidone, E-4031, and terfenadine) do not
dissociate from the closed (resting) channel state, whereas
[d] Prof. Dr. R. H. Guy
National Institutes of Health
Laboratory of Cell Biology, NCI, Bethesda, MD 20892-5567 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.200900374.
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The hERG K+ Channel and Drug Trapping
Table 1. hERG assay results for propafenone derivatives.
Compound
Structure
IC50 [mm][a] Trapped
Scheme 1. Synthesis of propafenone derivatives 3a–d.
3.95ꢁ
Yes
Propafenone
2.05
hydrochlorides by using standard procedures. Compounds 3a
and 3d were prepared as previously described.[20–22]
hERG K+ channel homology models
1.17ꢁ
Yes
3a
The open-state homology model of the hERG channel was ob-
tained with the crystal structure of KvAP as previously de-
scribed.[23] The four Tyr652 and four Phe656 residues make
concentric rings, as mentioned above. The first ring is formed
by the four Phe656 groups and is located at the cytoplasmic
side of the hERG channel. The planes of the four aromatic resi-
dues are parallel to the axis of the channel. The second ring is
made by the four Tyr652 groups, which face the inner cavity
like Phe656, but their aromatic residues are neither parallel nor
perpendicular to the channel axis. The amino acids Thr623,
Ser624, and Val625 are placed under the selectivity filter and
delimit the top of the inner cavity. The hydroxy groups of
Thr623 and Ser624 face the inner cavity, and they can be in-
volved in hydrogen bonding with potent hERG blockers.[14,24]
The closed-state homology model of the hERG channel was
obtained with the same procedures as for the open conforma-
tion. An initial model was generated by using the crystal struc-
ture of KcsA (PDB ID: 1K4C[25]). The alignment used for generat-
ing the resting-state model is given in the Supporting Informa-
tion. Details for modeling the S5 P-linker can be found in the
report by Tseng et al.[23]
0.29
5.41ꢁ
No
3b
1.01
2.09ꢁ
No
3c
0.55
3d
Inactive
ND[b]
In transition from the open to the closed state, the move-
ment of residues Thr623, Ser624, and Val625 is very small, and
so these amino acids are in the same positions in both the
open- and closed-state homology models. In contrast to the
top of the open-state model, the closed-state model exhibits a
significant movement of the S5 and S6 domains, which close
the inner pore. In the closed state, the aromatic ring plane of
Tyr652 is oriented perpendicular to the axis of the channel
with the hydroxy group directed away from the hERG channel,
whereas Phe656 has the same orientation as in the open state.
From the open state to the closed state, the distances be-
tween the Ca atoms of Phe656 and Tyr652 residues from op-
posite subunits decrease from 15.6 to 9.4 ꢂ and from 19.3 to
14.3 ꢂ, respectively. This also results in a >30% decrease in
the volume of the inner cavity, from 1642.2 ꢂ3 in the open
state to 1048.2 ꢂ3 in the closed state.
[a] Values are the mean of three experiments and were measured in heter-
ologous hERG expressed in X. laevis oocytes.[15,19,44] [b] Not determined.
show different trapping behaviors. The n-propylamino-
propafenone and the piperidine analogue 3a are trapped, the
two xylylpiperazine analogues 3b and 3c are non-trapped.
The highly hydrophilic morpholine 3d is inactive. Half-maximal
inhibition of hERG channels was estimated as peak tail current
inhibition (Figure 1A,B). Classification of drug trapping was
mainly set by assessing recovery from block at rest. For this
purpose, channel block was induced by applying 1 Hz condi-
tioning trains until steady state was reached. hERG currents
were subsequently measured after a rest period of 330 s at
ꢀ80 mV resting potential. hERG channels recovered from block
to a substantial extent (>65%) with compounds 3b and 3c
(Figure 1D), whereas negligible recovery (<5%) was observed
in the presence of propafenone and compound 3a (Figure 1C).
Recovery from block indicates whether a compound dissoci-
ates from the closed channel state during the rest period, or if
it is trapped at channel closure.
Trapping of propafenone derivatives
In this study, a systematic analysis of use-dependency of chan-
nel block and recovery from the block was performed for a set
of five propafenone derivatives (Table 1). Four out of five deriv-
atives tested exhibit only small differences in IC50 values, but
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G. F. Ecker et al.
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0.29 mm, trapped within the hERG channel). An alignment of
hERG open state docked conformations of propafenone and
3a is given in Figure 4A below, and shows a good overlap of
both structures.
Compound 3c (hERG IC50 =2.09ꢁ0.55 mm, non-trapped) is
unable to dock into the fully closed pocket of the hERG chan-
nel. This molecule bears a 2,3-dimethylphenyl-1-piperazinyl
ring instead of propylamine (propafenone) and piperidine 3a.
This moiety leads to an increase in molecular volume; this in-
crease in steric bulk may render the compound too large to fit
into the closed state of the channel. However, when docked
into the central cavity of the open state, 3c showed a position-
ing similar to that of propafenone (Figure 4B) and 3a (Fig-
ure 4C), with the 2,3-dimethylphenyl ring placed at the
bottom of the hERG channel cavity (Figure 3A,B). The docking
pose of the des-benzyl analogue 3b (hERG IC50 =5.41ꢁ
1.01 mm, non-trapped) also places the 2,3-dimethylphenyl ring
near the cytoplasmic side (Figure 3C and Figure 4D). Although
3b lacks one phenyl ring, the hERG non-trapping property of
this compound is maintained despite this decrease in molecu-
lar volume. These docking results indicate that electrostatic in-
teractions play an important role in drug trapping, because, to-
gether with the movement of S6 helices upon channel closure,
the protonated nitrogen atoms tend to move up near the base
of the K+ selectivity filter (Figure 5).
Figure 1. A) Current traces recorded in the absence (control) and presence
of increasing concentrations of compound 3b. The voltage protocol is
shown as inset at the top. B) Concentration–response relationship for block
of hERG tail current by compound 3b. C) and D) Recovery of hERG channels
from block. Channel block was induced by 1 Hz conditioning pulse trains to
reach steady-state. Superimposed current traces are sourced from 1) drug-
free control conditions (control), 2) the last pulse of the conditioning train
(block), and 3) a single test pulse after a rest period of 330 seconds at
ꢀ80 mV (recovery, dotted line). Recovery from block was measured in the
continued presence of drug. Lack of recovery from block is shown in C) for
compound 3a (4 mm) and recovery from block is illustrated in D) for com-
pound 3c (6 mm).
Several studies have already shown that the sodium channel
blocker propafenone also interacts with the hERG potassium
channel.[16,27–31] Witchel et al. performed detailed alanine scan-
ning studies, and docking of propafenone into the open and
closed state of the channel provided initial evidence that the
drug is trapped within the inner cavity.[16] Their data suggest
that the drug–channel interaction is strongly dependent on
residue Phe656, but is only weakly sensitive to mutation of
Tyr652, Thr623, Ser624, Val625, Gly648, or Val659.[16] The main
poses we obtained are in agreement with the results of Witch-
el et al., in the sense of the important interaction between
propafenone and Phe656 (which may involve p-stacking inter-
actions with two or more Phe656 side chains) in the open
channel model. However, our docking studies further indicate
that propafenone binding to the hERG open state may also in-
volve other amino acids, such as Thr623 and Ser624. Our re-
sults also indicate that the protonated nitrogen atom not only
interacts via cation–p interactions with Phe656, as commonly
postulated, but also shows interactions with Thr623 and/or
Ser624, as proposed by Farid et al.[26] and Choe et al.,[32] for ex-
ample.
Docking studies of propafenone derivatives on hERG
The parent compound propafenone was successfully docked
into homology models of the open and closed states of hERG
channels. For the closed state, the aromatic rings, particularly
the phenyl ring, show contacts with two Tyr652 residues (Fig-
ure 2A,B). Furthermore, six hydrogen bonds are predicted be-
tween propafenone and the hERG potassium channel; these
include two between the hydroxy group of propafenone and
Thr623, two between H of the basic nitrogen and Thr623/
Ser624, one between the basic nitrogen and Ser624 (not
shown in the 2D interaction map), and one between the car-
bonyl oxygen atom and Ser624. In docking propafenone into
the hERG open state, it was observed that the basic nitrogen
moves downward to the cytoplasm, and the nitrogen atom no
longer shows interaction with Thr623 and Ser624 (Fig-
ure 2C,D). Thus, during channel closure the basic nitrogen of
propafenone seems to move “up” toward the selectivity filter.
This movement may be facilitated by the negative field pro-
posed by Farid et al.,[26] which is located within the pore. Simi-
lar docking results were obtained for 3a (hERG IC50 =1.17ꢁ
In comparing the structures of the four ligands that bind to
the hERG channel, the two that are non-trapped both have a
large substituent at the nitrogen atom. Although the data set
is by far too small to derive any hypotheses that link drug trap-
ping with molecular features, this may be an initial hint that
the size of the substituent at the positively charged nitrogen
atom plays a role for trapping/non-trapping.
Following the commonly accepted hypothesis of channel
blocking, compounds cross the plasma membrane and contact
the hERG channel from the cytoplasmic side.[18] Upon opening
of the channel, compounds gain access to the binding site in
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The hERG K+ Channel and Drug Trapping
Figure 2. Binding pose of propafenone in the central cavity of hERG homology models in A) closed and C) open states, and 2D ligand interactions of propafe-
none for B) closed and D) open states. The amino acid residues that form hydrogen bonds within the binding site are represented as sticks, and the ligands
are rendered in capped stick. Dotted lines represent hydrogen bonding interactions.
the hERG central cavity. When the channel closes, major rear-
rangements of the binding site occur. Compounds that are
small enough (propafenone, 3a) may alter their conformation
and interaction pattern to fit into the closed pocket. In the
case of compounds with large substituents at the nitrogen
atom, such as 3b and 3c, these substituents may prevent the
channel from complete closure and thus allow the dissociation
of the compounds from the “closed” state. This type of “foot in
the door” mechanism has been postulated by Decher et al. for
AVE0118 on the Kv1.5 channel,[33] and seems to be valid for
propafenones as well.
binding affinities between ligands and target proteins. For the
hERG channel, several docking studies have been pub-
lished[12,16,26,34–40] that clearly indicate that small and large hy-
drophobic compounds bind to the hERG channel at various re-
gions of the central cavity. This definitely complicates the
proper prediction of both binding pose and affinity. Further-
more, the dynamics of the channel must be considered, and
docking experiments with different channel states have to be
performed. Thus, in order to elucidate the molecular basis of
ligand–channel interaction and to shed more light on the phe-
nomenon of drug trapping, it is necessary to combine ligand-
and target-based methods with the full armory of biochemical
tools, such as cysteine scanning and site-directed mutagenesis.
The primary goal of docking studies is the modeling of small
molecules within the protein binding site and the prediction of
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G. F. Ecker et al.
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Figure 3. Binding pose of 3c in the central cavity of the hERG homology model in the A) open state and B) its 2D ligand interaction pattern. C) 2D ligand in-
teraction of 3b with the hERG open state as generated by MOE. The amino acid residues that form hydrogen bonds within the binding site are represented
in stick form, and the ligands are rendered in capped stick. Dotted lines represent hydrogen bonding interactions.
Figure 4. Superposition of docked conformations into the hERG open state.
A) Propafenone (gray carbon) and 3a (green carbon); B) propafenone and
3c (magenta carbon); C) 3a and 3c; D) 3c and 3b (orange carbon). Colors
of other atoms are red for oxygen and blue for nitrogen.
Figure 5. Relative position of the nitrogen atom of 3a in the closed and
Combining data from all these experiments will improve our
open state. Complexes hERG–3a of open state (in black line) and closed
knowledge about the drug–channel interaction and enable the
state (in secondary structural color line) were aligned. Orange ball: nitrogen
development of predictive classification and regression
models.[7,41,42]
of 3a in the hERG open state (green carbon); blue ball: nitrogen of 3a in
the hERG closed state (magenta carbon).
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The hERG K+ Channel and Drug Trapping
for C30H36N2O3: C 76.24, H 7.68, N 5.93, found: C 75.81, H 7.68, N
5.76.
Conclusions
In this work, a small set of propafenone derivatives were syn-
thesized and biologically tested for hERG activity with special
emphasis on use-dependency of the channel block and recov-
ery thereof. Ligand–protein docking into homology models of
the closed and open state of the hERG channel provides the
first evidence for the molecular basis of drug trapping. Notably,
docking into protein homology models, especially into models
of promiscuous proteins such as hERG and P-glycoprotein, is a
rather uncertain process and needs careful validation. However,
in our case the docking results are so far consistent with the
experimental findings obtained. This information may provide
potential strategies for improving the performance of in silico
models for prediction of hERG activity, and should facilitate our
understanding of the molecular basis of drug–channel interac-
tions.
Propafenone, 3a, and 3d were prepared according to published
protocols.[20–22]
hERG assays
Molecular biology: Preparation of stage V–VI oocytes from Xeno-
pus laevis (NASCO, Fort Atkinson, WI, USA), synthesis of capped
runoff complementary RNA (cRNA) transcripts from linearized com-
plementary DNA (cDNA) templates and injection of cRNA were per-
formed as described previously.[15] cDNAs of hERG (accession
number NP_000229) were kindly provided by Dr. Sanguinetti (Uni-
versity of Utah, Salt Lake City, USA).
Voltage clamp analysis: Currents through hERG channels were
studied 1–4 days after microinjection of the cRNA using the two-
microelectrode voltage clamp technique. The bath solution con-
tained 96 mm NaCl, 2 mm KCl, 1 mm MgCl2, 5 mm HEPES, 1.8 mm
CaCl2 (pH 7.5, titrated with NaOH).
Voltage-recording and current-injecting microelectrodes were filled
with 3m KCl and had resistance values between 0.3 and 2 MW. En-
dogenous currents (estimated in oocytes injected with water) did
not exceed 0.1 mA. Currents >3 mA were discarded to minimize
voltage clamp errors. A precondition for all measurements was the
achievement of stable peak current amplitudes over periods of
15 min after an initial run-up. All drugs were applied by means of a
new perfusion system enabling solution exchange within
~100 ms.[43]
Experimental Section
Chemistry
Melting points were determined on a Reichert–Kofler hot-stage mi-
croscope and are uncorrected. Elemental analyses were performed
by the Microanalytical Laboratory, Institute of Physical Chemistry,
University of Vienna. NMR spectra were recorded on Bruker Specto-
spin (200 MHz). Column chromatographic separations were per-
formed with Merck Kieselgel 60 (70–230 mesh). Yields given below
are not optimized and refer to analytically pure material.
The pClamp software package version 10.1 (Axon Instruments Inc.,
Union City, CA, USA) was used for data acquisition. Microcal Origin
7.0 was employed for analysis and curve fitting.
General procedure for the synthesis of the tertiary amines 3b
and 3c: Epoxide 2 (17.7 mmol),[20–22] and the respective amine
(20 mmol) were dissolved in CH3OH and held at reflux for 6 h. The
mixture was evaporated to dryness, and the oily residue was puri-
fied by column chromatography (silica gel, CH2Cl2/CH3OH/concd
NH4OH, 200:10:1). The formation of hydrochlorides was carried out
by dissolving the amine in dry Et2O and adding a 1m solution of
HCl in Et2O. The hydrochloride was filtered off and purified by crys-
tallization.
Voltage protocol: The voltage protocol (see inset in Figure 1A)
was designed to simulate voltage changes during a cardiac action
potential with a 300 ms depolarization to +20 mV (analogous to
plateau phase), a repolarization for 300 ms to ꢀ40 mV (inducing a
tail current) and a final step to the holding potential. The +20 mV
depolarization rapidly inactivates hERG channels, thereby limiting
the amount of outward current. During the repolarization to
ꢀ40 mV, the previously activated channels open due to rapid re-
covery from inactivation. The decreases in the resulting tail current
amplitudes were taken as a measure of block development during
a pulse train.
1-[4-{3-[4-(2,3-dimethylphenyl)piperazin-1-yl]-2-hydroxypropoxy}-
phenyl)ethanone (3b): yield 52.8%; mp (HCl): 224–2258C; H NMR
1
(200 MHz, CDCl3): d=2.23 (s, 3H), 2.29 (s, 3H), 2.49 (s, 3H), 2.53–
2.91 (m, 10H), 3.47–3.70 (br, 1H, OH), 3.94–4.18 (m, 3H), 6.77–7.02
(m, 5H), 7.95 ppm (d, J=9.0 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=
14.3, 21.0, 26.7, 52.6, 54.2, 60.7, 65.7, 70.8, 114.6, 117.0, 125.5, 126.2,
131.0, 138.4, 151.7, 163.0 ppm; IR (KBr): n˜ =3440, 2941, 2817, 2360,
1675, 1600, 1509, 1473, 1455 cmꢀ1; MS (EI, 70 eV): m/z (%): 382 (3)
[M+], 203 (52), 189 (100), 146 (23), 118 (29), 91 (15), 70 (56); Anal.
calcd for C23H30N2O3: C 72.22, H 7.91, N 7.32, found: C 71.96, H
7.96, N 7.57.
Estimation of half-maximal inhibition of hERG channels: hERG
channel block was estimated as peak tail current inhibition (Figur-
e 1A,B). The concentration–inhibition curves were fitted using the
Hill equation:
IhERG;drug
IhERG;control
100 ꢀ A
¼
þ A
C
nH
1 þ ðIC
Þ
50
1-[2-{3-[4-(2,3-dimethylphenyl)-1-piperazinyl]-2-hydroxypropoxy}-
in which IC50 is the concentration at which hERG inhibition is half-
maximal, C is the applied drug concentration, A is the fraction of
hERG current that is not blocked, and nH is the Hill coeffi-
cient.[15,19,44]
phenyl]-3-phenylpropan-1-one (3c): yield 63.4%; mp (HCl): 165–
1
1668C; H NMR (CDCl3): d=2.21 (s, 3H), 2.27 (s, 3H), 2.38–2.85 (m,
10H), 2.97 (t, J=7.5 Hz, 2H), 3.35 (t, J=7.5 Hz, 2H), 3.05–3.85 (br,
1H, OH), 3.89–4.05 (m, 3H), 6.82–7.31 (m, 10H), 7.39 (dt, J=1.5,
7.8 Hz, 1H), 7.63 ppm (dd, J=1.5, 7.8 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d=14.3, 21.0, 30.7, 46.1, 52.6, 54.0, 61.3, 65.6, 71.2, 113.0,
117.0, 121.4, 125.5, 126.2, 126.3, 128.6, 128.8, 130.9, 131.6, 133.9,
138.4, 142.1, 151.7, 158.2, 201.6 ppm; IR (KBr): n˜ =3460, 2818, 2350,
1668, 1597, 1473, 1450 cmꢀ1; MS (EI, 70 eV): m/z (%): 472 (2) [M+],
203 (100), 189 (28), 160 (17), 132 (13), 91 (17), 70 (65); Anal. calcd
Molecular modeling and docking studies
Preparation of molecular structures: The structures of propafe-
none and its derivatives were built in MOL2 format using the
sketcher module of Sybyl, and Gasteiger–Hꢃckel charges were as-
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signed to the ligand atoms. The structures of the molecules were
optimized by energy minimization and molecular dynamics using
the simulated annealing method.[45] The lowest-energy conformer
of each molecule was selected, and a formal charge of +1 was as-
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Preparation of target protein structure and flexible docking:
Docking studies were performed on two homology models of the
hERG potassium channel: one in an open conformation and the
other in a resting state conformation.[23] The active site was defined
by all the amino acid residues within a sphere of radius 6.5 ꢂ cen-
tered by several residues known to have an important role for
drug binding. The docking and subsequent scoring were per-
formed with the default parameters of the FlexX programs imple-
mented in the Sybyl 7.0 software package.[45] Final scores for all
FlexX solutions were calculated by the standard scoring function
and used for database ranking; 2D ligand interactions were gener-
ated with the MOE software package.[46]
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[24] K. Kamiya, R. Niwa, M. Morishima, H. Honjo, M. C. Sanguinetti, J. Phar-
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Keywords: docking · drug trapping · hERG · ion channels ·
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Received: September 4, 2009
Revised: January 9, 2010
Published online on February 9, 2010
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