Advanced Molecular Modeling Techniques Applied to Ion Channels Blockers - Ion Channels and Their Inhibitors - page 58

N -phenyl ring forms intermolecular hydrogen bonds to the backbone NH group and
the orientation of the ortho -methyl substituent toward the backbone NH group [ 29 ].
That structural information at the molecular level can be obtained, which are
helpful to understand the fundamental mechanism of chemical events occurring as
these insights can aid the design of novel ion channels blockers. Several established
approaches in computational chemistry include; quantum calculations, molecular
simulations, molecular docking or screening and structure-activity relationship
(SAR), which can prove highly beneficial during the pharmaceutical development
process. The number of molecular modeling publications in the ion channel area is
~550 papers at present and ~60 for channel based on searches of the Scopus
database ( http://www.scopus.com ). In this article, we focus on a number of signifi-
cant modeling examples to exemplify the current state of the art in the field.
2 Molecular Docking of the Ion Channels Blockers
Molecular docking is of fundamentally importance in modern structure-based drug
design due to its ability to predict accurate binding modes of a ligand inside a given
receptor [ 30 ]. The method relies on sampling conformational space of the ligand
within protein environment, driven by a conformational searching algorithm and a
scoring function. Two popular searching strategies that have been proposed are
incremental construction algorithm [ 31 ] and genetic algorithm (GA) [ 32 ]. A scoring
function involves energetic calculations for ranking different poses of ligand, which
are derived from either molecular mechanics [ 33 - 35 ] or empirical free energy [ 36 ].
The pharmaceutical major interested is to identify the interactions between
blockers and protein channels. When the binding mechanism of blockers have not
been solved yet, several questions remain unclear such as where is the most
favorable binding site, how the blockers generally bind, which other types of ligand
can bind, what are the key residues, etc. Molecular docking is an approach to
answer to these questions. For instance, molecular docking has revealed the
blocking site of Kir2.1 potassium channel [ 37 ], hERG potassium channel [ 38 ],
GABA receptor [ 39 ], Torpedo nicotinic acetylcholine receptor [ 40 ], and suggested
the binding conformation of the flexible blockers such as hanatoxin [ 41 ],
bupivacaine [ 42 ], sertindole [ 43 ], and psalmotoxin-1 [ 44 ]. The key residues of
the protein channel for the binding of ligands can be revealed when incorporating
molecular docking with MD simulations [ 43 , 45 - 47 ].
The molecular docking approach has a significant impact on high-throughput
virtual screening to search for novel blockers of ion channels [ 48 , 49 ]. Not only
these characters were explored by molecular docking, but also new docking
techniques for the ion channel blockers were introduced [ 50 ]. Moreover, mole-
cular docking often generates the initial complex geometry used for later MD
simulations.