Advanced Molecular Modeling Techniques Applied to Ion Channels Blockers - Ion Channels and Their Inhibitors - page 65

placed K + ion and water in a specific site [ 37 ], for example, the 1010 state is where
K + ions were present at the first and third positions of the selectivity filter [ 45 ]. The
channel models are usually merged into lipid bilayer of 1-palmitoyl-2-oleoyl-sn-
glycero-3-phosphocholine (POPC) and solvated by SPC or TIP3P water model
[ 75 ]. After the channel is inserted into the lipid bilayer, counter ions and water
should be added, that is 102 mmol/dm 3 ion concentration for Kir2.1 channel [ 37 ].
Without the lipid membrane, restraining forces need to be applied to the ion channel
peptide backbone to maintain structural stability. High temperature of 700 K can be
used [ 78 ]. In terms of solvation, a periodic cubic box is preferable to an octahedral
box [ 78 ]. For the equilibration process, a restraint is usually applied on channel
backbone or alpha carbon while temperature of the system is heated to 300 K [ 49 ].
If a simulation sphere is considered [ 45 ], multilevel restraint forces may be applied
with a certain region such as a radius of 30-35 ˚ from the binding site and a force
constant of 10 kcal/mol on the intermediate region and a force constant of 100 kcal/
mol [ 42 ] on the outer 35 ˚ region. As the channel consists of bundles of transmem-
brane helices, constraints may be applied to keep the channel symmetry as C5
symmetry in the case of

) for example [ 72 ]. The force field
applied to simulate the channel can be the united atom Gromos-87 [ 42 ], OPLSAA
[ 49 ] and AMBER99 [ 40 ]. In the production dynamics phase, bond constraint by
SHAKE or LINCS algorithms is used [ 49 ]. After minimization with or without
restraint, and equilibration at 300 K, the production phase was carried at 8-10 ns.
MD simulations with the multiple time step method can be an alternative approach
to study the binding between ligand and ion channel, where non-bonded inter-
actions are divided into multiple regions. According to the multiple time step
approach, time step of 1 and 2 fs are applied for intramolecular and intermolecular
force, respectively, to observe the impramine/nAChR binding. Several energy
evaluation methods are used in the biomolecular system such as thermodynamic
integration (TI), molecular mechanic/Poisson Boltzmann surface area (MM/PBSA)
and scoring function, however, to quantify the binding between blocker and the ion
channel, are mostly determined by MD/LIE calculations [ 42 , 43 , 45 ] because of its
compensation between simplicity and accuracy over others.

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4 QSAR Study on Ion Channels Blockers

Quantitative structure-activity relationships (QSARs) [ 79 ] are mathematical model
that describe the relationship between the structure and physical properties of
chemicals and their biological activities. This method has been highly utilized in
the drug design area. QSAR studies have been reported to identify important
structural aspects associated with the inhibition of human ion channels blockers
located in heart tissue [ 80 - 86 ]. The obtained results illustrate the applicability of
binary QSAR methods for the classification of the human ether-a-go-go related
gene (hERG) potassium channel blocker activities and for identification of potential
toxicity risks [ 87 ]. The drug-related adverse events (AEs) were highly correlated