(A)
(B)
(C)
LP
0.14
0.12
0.09
0.07
0.05
0.03
0.01
Leu547
Thr550
-0.02
-0.04
-0.06
Leu515
-0.08
-0.11
-0.13
Tyr511
-0.15
-0.17
-0.19
Ser512
Figure 2. Flexible docking result of 15 in the hTRPV1 model
(A) Binding mode of 15. The key interacting residues are marked and displayed as a capped-stick with carbon atoms in white. The helices are colored in gray and
the helices of the neighboring monomer are displayed as a line ribbon. The ligand is depicted as a ball-and-stick with carbon atoms in magenta and its van der
Waals surface is presented with lipophilic potential property (LP) which ranges from brown (highest lipophilic area) to blue (highest hydrophilic area). Hydrogen
bonds are drawn in black dashed lines and non-polar hydrogens are undisplayed for clarity. (B) Surface of hTRPV1 and 15. The Fast Connolly surface of
hTRPV1 was generated by MOLCAD and colored by the lipophilic potential. For clarity, the surface of hTRPV1 is Z-clipped and that of the ligand is in its
carbon color. (C) Lipophilic potential property of 15.
In order to investigate the key interactions of compound 15
with the receptor, we carried out the docking study of compound
15 with the human TRPV1 homology model, which was built on
our rat TRPV1 homology model as reported recently11 and
modified to include the sequence differences between rat and
human TRPV1 in the vicinity of the binding site. As shown in
Figure 2, compound 15 fitted well to the binding site of hTRPV1
which has a deep bottom hole, surrounded by Tyr511 and
Ser512, and an upper hydrophobic region containing Leu547.
The isoquinoline group of 15 in the A-region occupied the deep
bottom hole and formed a hydrogen bonding with Ser512. In
addition, its urea group as the B-region interacted with Tyr511
by hydrogen bonding. The C-region of 15 oriented toward the
upper region of the binding site and the hydrophobic CF3 group
fitted very well, making the hydrophobic interaction with
Leu547. This docking result identified binding interactions
between the three regions of 15 and hTRPV1 and the high
potency of 15 can be understood in terms of criticial hydrogen
bonding between the isoquinoline nitrogen and Ser512.
Acknowledgments
This research was supported by Grants from Grunenthal, the
Korea Health Technology R&D Project (HI13D2358), National
Research Foundation of Korea (R11-2007-107-02001-0), the
National Leading Research Lab program (2011-0028885), and in
part by the Intramural Research Program of NIH, Center for
Cancer Research, NCI (Project Z1A BC 005270).
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In summary, we have investigated a series of N-[{2-(4-
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