Biomedical Engineering Reference
In-Depth Information
6 Quantum Chemical Calculations of Ion Channels Blockers
6.1 Applications of Ab-Initio and DFT Methods
Quantum chemical (QC) calculations while not so frequently used in drug discov-
ery due to their computation costs are nonetheless important tools in computer-
aided drug design research. The use of QC calculations provides a more accurate
description of how molecules interact and their three-dimensional conformation,
which in turn is important in determining their biological function. This approach
can therefore also show the connecting link between experimentally determined
structures and biological function.
QC calculations can be used to understand ion channels mechanism of action,
hydrogen bonding, polarization effects, spectra, ligand binding and other funda-
mental processes both in normal and in aberrant biological contexts. With the
advancement of parallel computing and progress in computer algorithm design,
more realistic models of ion channel and its blockers are possible. For example,
Density Functional Theory (DFT) based on B3LYP/6-31G (d,p) calculations were
used for identification of the receptor site for the blocking of the voltage depen-
dent K+ channels by protonated aminopyridines [
118
], and calculate the geometry
of alkaloids obtained from
Aconitum
and
Delphinium
sp. [
119
]. Furthermore,
specific DFT calculations of charged ryanodine receptor (RyR) calcium channel
were used to study the binding energy and selectivity of Ca
2+
versus monovalent
cations [
120
].
The precise conformation of a blocker is important for binding to all receptors
including ion channels. The complementarity of molecular surfaces and electro-
static potentials between ligand and the receptor site is essential for forming stable
low binding energy complexes, as the total binding energy results from the local
interactions between each part of the ligand and the surrounding protein. For
instance, conformational properties and partial atomic charges of bupivacaine
were determined from quantum chemical calculations at the HF/6-31G* level
with inclusion of solvent effects. The binding of bupivacaine to the KcsA structure
was found to prefer the closed channel state [
121
]. Another example can be
appreciated by considering the Ab-initio Hartree-Fock molecular orbital calcu-
lations, which produced complete geometry optimizations on some phenylalk-
ylamines (PAAs) [
122
].
In case of the Ca
2+
-benzene complex, optimized in the gas phase using the
Hartree-Fock model with the split valence 6-311G** basis set, it was found that the
attraction between small metal cations and an aromatic residue would enhance
single-channel conductance [
123
]. Another important example that demonstrates
the utility of QC methods is in modeling the carbonyl oxygen atoms that surround
permeating ions is the most important factor in determining ion selectivity rather
than the size of the pore or the strength of the coordinating dipoles. Geometry
optimizations were performed at the HF level using the 6-311G* basis set, and final
interaction energy calculations were made using MP2/6-311G* with counterpoise
