Biomedical Engineering Reference
In-Depth Information
discovery process [
69
-
72
,
83
,
84
]. These models are useful because they rationalize
a large number of experimental observations, and allow saving of both time and
money in the drug design process, and represent a step forward in the in silico
identification of potent NCC blockers.
The lessons learned from the QSAR analysis is that mapping the chemical space
of known NCC blockers has shed some light on the structural aspects of ligands
consistent with the channel blocker profile. Also, we have noticed that large number
of diverse class of NCC blockers have high flexible linkers and connect various
molecular fragments. Due to the high flexibility of the NCC blockers, the bioactive
conformation adopted seems to be compatible with the large binding pore region in
the channel. Thus, blocker rigidification seems to be a proper solution for
overcoming the channel complexity.
Also, much information exists for blockers of NCC with different structural
diversity. The ongoing medicinal chemistry optimization program to synthesize
potent leads has direct impact on this information. The computational model based
on literature data therefore provides a potentially valuable tool for discovery
chemistry as future compounds may be synthesized that are potent NCC blockers.
The scope of our 2D-QSAR model [
71
] is interesting in light of the complexity of
the NCC states. Possibilities for additional physicochemical features not covered by
our QSAR models are entirely plausible given the complexity of the NCC, its state-
dependent conformational changes, and its interactions with the membrane and
other proteins. Furthermore, factors such as membrane permeation required for
accessing the intracellular lumen of the NCC and possible shifts in local p
K
a due to
changes in membrane potential further complicate the problem of predicting NCC
inhibitory activity. The ability to locate and describe these alternative NCC active
sites is likely to come from a concerted effort of in vitro, in vivo, and in silico
experiments such as site-directed mutagenesis, radioligand competition assays,
theoretical channel modeling, and ultimately membrane structural biology.
The present results can be used to flag commercial libraries overly enriched with
predicted NCC platform-specific channel blockers. In addition to this the in vitro
and in vivo models are very labor-intensive, expensive, and not widely available.
Nevertheless, it is hoped that our 2D-QSAR model can be used as a preliminary
guidance for explaining NCC liabilities in early lead candidates as well as for
designing out properties that promote NCC blocking in such compounds [
71
].
6 Need for NCC Blockers
Pain is an unpleasant sensory and emotional experience associated with actual or
potential tissue damage. Depending on the etiology and pathophysiology, it is
categorized as acute pain and chronic pain. Acute pain is self-limiting and serves
as protective biological function by acting as a warning of on-going tissue damage,
while chronic pain is itself a disease process. Although acute pain may occur with
cancer and neurological diseases. Neuropathic pain is a common type of chronic
