Biomedical Engineering Reference
In-Depth Information
2.7 hERG K
+
Modulators
The hERG (human ether-`-go-go-related gene) potassium channel (Kv11.1) plays a
vital role in maintaining normal electrical activity in the heart [
17
]. It mediates the
repolarizing I
Kr
current in the cardiac action potential. The intended or unintended
inhibition of electrical conductance of hERG K
+
channel either by drugs or by gene-
mutation can cause serious disorder called long QT syndrome. Even several
clinically useful and approved drugs are known to show a tendency to inhibit
hERG K
+
channel conductance and thereby cause arrhythmias, and create a risk
of sudden death. For drug-induced QT prolongation, the increase in the duration of
repolarization through blockade of outward K
+
current is responsible. Thus, hERG
inhibition is an important anti-target, which must be avoided during drug develop-
ment [
68
].
The primary structural components in hERG are found to be a positively charged
S4 helix and a P-loop. Different hERG-ligand modeling studies have suggested that
Phe-656 and Tyr-652 residues are involved in hydrophobic interactions and Thr-623
and Ser-624 residues modulate the binding potency through the polar tails of hERG
blockers [
69
-
72
]. Also, results from some studies have favored multiple
pharmacophore models to explain the binding of high- and low-affinity ligands [
73
,
74
]. The in silico modeling studies of Borosy group [
75
,
76
]onhERGchannel
blockers have pointed out a five-point pharmacophore (hydrogen bond donor, hydro-
gen bond acceptor, two aromatic rings, and a hydrophobic aliphatic chain) model for
the most active molecules and a four-point pharmacophore model for the less potent
agents. The results from Ekins et al. also favored a five centered pharmacophore
model, where a positive center has separated from four hydrophobes at distances 5.2,
6.2, 6.8 and 7.5
˚
[
77
]. Cavalli et al. constructed another pharmacophore model
having three aromatic moieties connected through a nitrogen function (tertiary
amine) at distances of 5.2-9.1, 5.7-7.3 and 4.6-7.6
˚
[
78
]. These authors have also
reported several geometrical parameters such as angles, angle between the planes,
and the height above the planes of the pharmacophore.
Apart from the above reported findings on hERG, a CoMSIA study was reported
making use of its high affinity ligand. Sertindole (13) is an antipsychotic drug and
blocks hERG with high affinity [
79
]. Pearlstein et al. [
80
] carried out, using SYBYL
6.7.2 Tripos Inc. [
81
], a CoMSIA modeling of the hERG inhibitory activity of 22
sertindole analogues together with ten assorted compounds. These authors found a
complementary
N
NH
N
Cl
O
N
F
13
