Biomedical Engineering Reference
In-Depth Information
selectively to the carboxyl terminus of S3 segment (S3C) in voltage-gated potas-
sium (Kv) channel and have been studied by Lou and co-workers. Docking of the
helix drk1 S3C onto the HaTx1 generated several possibilities for the drk1 S3C
orientation. The best energetic configuration revealed that the important region of
interaction were the hydrophobic patch between drk1 and HaTx1. Therefore, the
hydrophobic Val271, Tyr274, Leu275 and Val282 of drk1 S3C should be located at
the boundary of membrane rather than located at the aqueous phase [
41
]. Move-
ment of drk1 S3C toward S4 upon conformational change of Kv channel occurs
after HaTx1 binding. Therefore, the structural roles of S3C-S4 proximity in inter-
fering with S4 translocation were investigated by docking shaker with HaTx1
comparing with drk1. A significant movement of drk1 S3C, but not the Shaker
S3C, in the direction presumably toward S4 during drk1 gating in the presence of
HaTx1 was suggested [
54
].
Docking scorpion toxin - charybdotoxin (ChTX), kaliotoxin (KITX), and
agitoxin (AgTX) - into the homology voltage-gated potassium channel (Kv1.3)
explained the pore model when positioning two contacts of toxin residues: the side
chain of Lys27 in its extended conformation into the central axis of the pore, and the
side chain of Arg24 in close steric contact with the carboxyl group of Asp386 of the
channel. The best conformation obtained after docking and minimization involved
interaction with Asp386 of the channel i.e., Arg24 of the toxin forms a hydrogen
bond with Asp386 of one subunit and Asn30 is in immediate contact with Asp386
of the opposing subunit in the tetramer [
55
].
Ten homology models of NR2B subunit in the NMDA receptor, composed of the
R1-R2 domain in the open and closed conformation, were created prior to dock the
ifenprodil. The binding pose of the ifenprodil antagonist for the NMDA receptors
(glutamate-gated ion channels, iGluRs) was revealed at the atomic level by
Marinelli and co-workers [
56
]. Further insight into the ifenprodil mechanism of
action was discovered by MD simulations followed by MM-PBSA calculations,
confirming that ifenprodil stabilized the closed conformation of the R1-R2 domain
[
56
]. The significant structural conformation of ligand was revealed when agonists
such as GABA and Muscimol were placed into the GABA
A
receptor model using
distance-screen filtration in easyDock program. Calculation of the electrostatic
potential complementarity is useful to discriminate multiple docked configurations
especially for charged ligands. Muscimol has greater affinity than GABA because
of its structural conformation, which sees the oxazolo ring sandwiched between the
faces of Tyr181 and Tyr229 in the bound state [
57
].
2.3 Discovery of Novel Blockers by Virtual Screening
Novel blockers can be obtained from several approaches including high-throughput
screening and combinatorial synthesis. A receptor-based virtual screening per-
formed by docking is an additional method to search for either novel ligands or
investigate novel binding pockets.
