Biomedical Engineering Reference
In-Depth Information
categorized according to their nature, such as constitutional, topological, geometri-
cal, electrostatic, quantum-chemical, and thermodynamic descriptors. 2D-QSAR
has been used on hERG channel blockers with diverse structures [
94
]. For example,
for 2D-QSAR of Tocainide and Mexiletine were studied using lipophilic and basic
molecular properties for voltage-gated sodium channels (VGSCs) [
98
]. 2D-QSAR
modeling was carried out on ion channels blockers of the inactive form of the
human skeletal muscle sodium channel isoform Na
v
1.4. The chemometric analysis
suggested that a pharmacophore hypothesis highlighting the structural charac-
teristics needed for an enhanced phasic block (PB) activity. Thus, it appears that
2D-QSAR models can help in determining which parts of a molecule can be modi-
fied to increase (or decrease) affinity and efficacy, providing valuable guidance
in the drug discovery process [
99
].
4.3
3D-QSAR of Ion Channels Blockers
The initial alignment of molecules is critical to the success of three-dimensional
quantitative structure-activity relationships (3D-QSAR) model such as Compara-
tive Molecular Fields Analysis (CoMFA). Therefore, in this regard, several
attempts have been made to find the most appropriate molecular alignment to
obtain more predictive models. Cavalli et al. (2002) attempted to develop a quanti-
tative model correlating the 3D stereoelectronic characteristics of a set of molecules
with hERG blocking activity [
89
]. They first considered an initial set of QT-
prolonging drugs for which the hERG potassium channel blocking activity was
measured on mammalian transfected cells. The models gave a general description
of the molecular features associated with the QT-prolonging ability as well as a
quantitative model to predict the hERG potassium channel blocking potential of
new compounds. The CoMFA model presented an acceptable level of predictivity
but cannot yet be proposed as a rapid and efficient in silico tool for the early
identification of the long QT syndrome (LQTS) inducing activity. Furutani et al.
(2009) demonstrated a 3D-QSAR model of antidepressants at the Kir4.1 channel,
which suggested that their structures share common features including a hydrogen
bond acceptor and positively charged moiety [
90
]. Additionally, they suggest that
this charged moiety interacted with the inwardly rectifying potassium (Kir) 4.1
channel pore residues by hydrogen bond and ionic interactions, which account for
preferential inhibitory action on Kir4.1 [
100
]. In particular, the presence of a polar
negatively charged group was predicted to be important
for
the general
pharmacophore associated with hERG blockage.
4.4
4D-QSAR of Ion Channels Blockers
In four-dimensional quantitative structure-activity relationships (4D-QSARs), each
blocker is represented an ensemble of different conformations, orientations,
