Biomedical Engineering Reference
In-Depth Information
inhibitory activity. The electrotopological descriptor S_sNH2 stands for sum
descriptor for nitrogen bonded to two hydrogens and one single bond and has
indicated that more number of features, such as nitrogen containing heterocyclic
moieties, are beneficial to the inhibitory activity. The descriptor ADMET_PPB
corresponds to likelihood of binding of the molecule to plasma proteins in the
threshold of 90-95%. The descriptor JX (Balaban index) reflects upon the relative
connectivity and effective size of the carbon chain to which multiple methyl groups
are attached. Here, an increase in number of methyl groups decreases the activity.
The Atype descriptors are thermodynamic descriptors, which define the presence of
the particular type of atom in the molecule. The negative contribution of descriptor
Atype_H_46 (hydrogen attached to Csp
3
0
) illustrates that inhibitory activity
decreases with increase in the hydrophobicity associated with this hydrogen.
Likewise Atype_O_57 and Atype_O_59 descriptors also showed a negative contri-
bution to activity. Here the 'O' in Atype_O_57 represents oxygen in phenol, enol,
and carboxyl OH and Atype_O_59 refers to oxygen in Al-O-Al (Al
aliphatic).
The negative contribution of Atype thermodynamic descriptors and that of topo-
logical Balaban index JX to inhibitory activity advocate that electronegative groups
in the ligand decrease the affinity for hERG K
+
channels.
Garg et al. [
82
] have further used these compounds (Table
1
) in HypoGen of
Catalyst to generate the toxicophore models. This has led to the identification of
three important features for hERG K
+
channel blockers. These features were
identified as (a) hydrophobic group, (b) ring aromatic group and (c) hydrogen
bond acceptor lipid group. The most predictive hypothesis has best explained the
activity and showed a low RMS deviation aswellashighcostdifference.Also,
both 2D-QSTR and toxicophore models have optimally predicted the hERG K
+
channel blocking activity of test set compounds [
82
]. Thus, this study has helped
in understanding the hERG K
+
channels affinity for different compounds
(Table
1
), and provided inputs to overcome the adverse structural features respon-
sible for the binding affinity and addressed the ways to mitigate the undesirable
side effects.
¼
3 Conclusions
Potassium ion channels play important role in a variety of diseases having direct
bearing on the quality of life. Cardiovascular, nervous, immune and endocrine
systems are a few critical organs/ systems among many others, which are affected
by these ion channels. In this background, maintenance of stasis of the ion channels
is curial for the health. Because the ion channels are ubiquitous in nature and highly
variable even within a given family, identification of drugs acting through them
with specificity and high therapeutic value is a challenge. From a broad perspective,
several of the chemical scaffolds discussed in this article share a large structure
space, at the same time each one has distinctly responded at the target in eliciting
the biological response. In this scenario, QSAR and modeling studies offer fast
