Biomedical Engineering Reference
In-Depth Information
(bound state) was extracted and minimized in water (free state) to obtain the
reference electrostatic and van der Waals energies. The difference in the computed
energy values (
vdw) between the bound and the free states were used to
derive linear regression fits to the experimental pIC
50
. The estimated interaction
energy was used to establish the preference of each ligand for one of the two
states. The computed pIC
50
values of the 21 ligands that prefer to bind the open-
state model were predicted with an RMSD of 1.2 [pIC
50Open
¼
D
ele and
D
D
0.166(
vdw) +
0.002(
ele)]. For the 11 compounds that preferentially interact with the partially
open-state model,
D
the pIC
50
values were calculated with an RMSD of 0.85
[pIC
50Closed
¼
ele)]. Given the fact that both models
had essentially the same coefficients for the (
D
vdw) term, a single model was
generated combining the energies for each ligand docked into its best fit state.
Plotting the experimental versus computed pIC
50
values five outliers were
identified. The model obtained [pIC
50Combined
¼
0.155(
D
vdw) + 0.0004(
D
ele)]
omitting those five outliers showed an RMSD of 0.56 and an
r
2
of 0.82. The
equation reveals that the most important contribution to the hERG affinity arises
from
0.163(
D
vdw) + 0.0009(
D
vdw, in agreement with the previous observations, which indicated that
hydrophobicity and aromaticity were the most important physicochemical features
of Phe656 and of Tyr652, respectively [
103
].
¨
sterberg et al. [
98
] used molecular dynamics (MD) simulations and the linear
interaction energy (LIE) method to calculate the binding affinity of six sertindole
analogues docked into the homology model of the hERG channel in the open state.
For each ligand, the pose with the lowest energy was selected from the two or three
best clusters, and was submitted to molecular dynamics (MD) simulations. The K
þ
ions can occupy the selectivity filter with the 1010 (K
þ
-H
2
O-K
þ
-H
2
O) or with the
0101 (H
2
O-K
þ
-H
2
O-K
þ
) configurations. The binding free energies for hERG
indicated that the 1010 is the most favorable conformation. The higher value of
binding free energies obtained with the 0101 configuration is due to the electrostatic
repulsion between the basic nitrogen of the blocker and the K
þ
ion facing the
central cavity. The plot of the calculated LIE free energies versus the experimental
values shows a good correlation between these two terms.
Also, Farid et al. [
99
] obtained a good correlation between the predicted and the
experimental ligand binding free energy of four sertindole analogs. The compounds
were docked into the homology model of the hERG channel in the open state using
the induce-fit protocol. The correlation between the Extra Precision (XP) scoring in
Glide and the experimental binding affinity shows an
r
2
of 0.95. The analysis of the
terms of the Extra Precision (XP) scoring indicates that the Glide-XP lipophilic
contact and the Glide-XP van der Waals energy terms are favorable for hERG
inhibitors, while the Glide-XP penalty for buried polar groups term is unfavorable.
The GOLD docking software was used to dock 56 known blockers into a closed-
state model [
92
]. For each ligand, the best pose was selected and the docking
GOLDScore fitness was used to derive a linear regression fit to the experimental
pIC
50
. The model achieved an
r
2
of 0.60 and a
q
2
of 0.56, demonstrating that it can
be used to predict the binding affinity of hERG inhibitors.
D
