Biomedical Engineering Reference
In-Depth Information
with an external test set of 12 molecules, the QSTR model shows an
r
2
value of
0.70. The importance of the Kappa-3 descriptor might indicate that the molecular
shape can play a role in the hERG interaction. The S_sNH2 descriptor highlights
that the presence of a primary amine group increases hERG inhibition. The Balaban
index is inversely correlated with hERG potency, indicating that it might be
possible to decrease the activity of hERG blockers by increasing the branching of
the molecule. All the A-type descriptors are negatively correlated with the inhibi-
tion of the hERG channel. This suggests that hERG potency decreases by adding
electronegative groups.
Shamovsky et al. [
38
] studied hERG selectivity of four classes of chemokine
receptor (CCR) ligands. In this study, the baseline lipophilicity relationship (BLR)
approach was used to increase the hERG selectivity of compounds. Mathemati-
cally, the BLR is:
pIC
50
¼
a
log
D
k
D
G
intr
þ
const,
(1)
pIC
50
¼
potency of the compound;
a
¼
hydrophobicity factor of the binding
site;
D
¼
n
-octanol/water partition coefficient;
D
G
intr
¼
intrinsic binding energy
RT
)
1
.
nonrelated with the desolvation;
k
¼
coefficient equal to (2.303
log
D
is the lipophilicity driven component of potency caused by
desolvation. The second term -
k
The term
a
G
intr
is the intrinsic potency, which depends
on the molecular interactions of the ligand with the target. When the hERG
selectivity of the compound (C) is taken into consideration, the equation becomes:
D
pIC
50
pIC
hERG
50
pIC
50
a
hERG
G
hERG
intr
¼
log
D
þ
k
D
þ
const
(2)
G
hERG
intr
The term
k
D
does not depend on the interactions with the primary
log
D
(lipophilicity-adjusted primary potency)
is independent on the hERG binding affinity. The lipophilicity-adjusted hERG
potency pIC
hERG
50
target. The term pIC
50
a
hERG
log
D
was used in a fragment-based QSAR analysis
to identify moieties that form important nonhydrophobic interactions with the
hERG channel. The fragment-based QSAR analysis in a given chemical series
ranks the fragments according to their contribution to the hERG potency. The
regression analysis using (1) shows that
a
hERG
is close to one for all four classes
of compounds. This means that if the lipophilicity increases by one unit, also the
hERG potency increases. Further analysis of (1) indicates that the lipophilicity has a
stronger influence on hERG potency than on hERG selectivity. This renders it quite
difficult to enhance the hERG selectivity by decreasing the lipophilicity, suggesting
that it is easier to improve the hERG selectivity by increasing the lipophilicity-
adjusted primary potency value.
In a follow-up study, Shamovsky et al. [
54
] used 464 CCR8 antagonists and
8 hERG mutants to increase the selectivity of the compounds toward the hERG
channel. A 2D fragment-based QSAR analysis performed on a subset of 25
spirocyclic CCR8 antagonists revealed that bulky and rigid substituents decrease
the hERG affinity due to van der Waals clashes with Phe656.
a
hERG
