Advanced Molecular Modeling Techniques Applied to Ion Channels Blockers - Ion Channels and Their Inhibitors - page 57

specific molecules before the channel opens and ion flux. An example of ligand-
gated ion channels is acetylcholine receptor (AChR), whereas acetylcholine is the
gating molecule for Na + flow [ 18 ]. The binding site for ligands is located between
the M2 subunit transmembrane region and extracellular loop C terminus [ 19 ].
1.3 Function of Ion Channels Blockers
Molecules that bind to ion channels resulting in the blockage of ion flux are termed
ion channels blockers. The blockage of cellular signaling is important in pharma-
ceutical therapies including antitumor agent such as astemizole or imipramine [ 20 ],
hypertension treatments [ 21 ] and decrease anti-inflammatory and bone resorption
or Periodontal Disease [ 22 ].
Blockage of the voltage-gated potassium channel Kv1.3 found in the effective
memory T cell (T EM ) is known to inhibit calcium signaling and cell proliferation
[ 23 ]. Therefore, Kv1.3 blockers such as clofazimine have been used to treat
sclerosis [ 24 ], graft-versus-host disease, cutaneous lupus, and pustular psoriasis
[ 25 ]. The ion channel activity in the presence and absence of a blocker can be
determined through the detection of the channel current using the patch clamp
technique [ 26 ]. Recently, the anti-neuroexciting properties of novel Na + channel
blocker was also assessed using whole-cell patch clamp recordings [ 27 ]. However,
insight into the binding of blockers at the molecular level can be only obtained from
computational methods at present.
1.4 Current Advanced Molecular Modeling Techniques
Applied on Ion Channels Blockers
Computational research on the ion channels has grown dramatically since the first
three-dimensional structure of the KcsA potassium channel was discovered in 1998
[ 1 ]. Molecular dynamics (MD) simulations of the KcsA potassium channel revealed
the origin of the selectivity of the channel for Na + and K + ions of the channel. The
complete solvation of the K + ions at the selectivity filter leads to the smaller passing
energy barrier than Na + ions as large as 12 kT. Investigation on the thermodynamics
using MD also suggested that the channel conductance is driven by the strength of
the electrostatic interactions with ions and dipoles of residues rather than ion
mobility itself [ 28 ].
In one of the earliest computational study of blockers, a simple molecular
mechanics protocol with MMP2 parameters was used to optimize a series of
4-amino- N -phenylbenzamides followed by Monte Carlo (MC) simulations, which
were compared with results from the maximal electroshock (MES) test. That study
suggested that the high anticonvulsant activity required conformations where the