Biomedical Engineering Reference
In-Depth Information
The pharmacophoric features of NCC blockers are case specific and depend on
the studied class of compounds. There exists structurally diverse class of NCC
blockers having different scaffolds with no representative structural moiety, which
includes (a) peptide and
L
-cysteine based moiety, (b) aryl heterocyclic moiety, (c)
arylsulfonamide moiety, (d) benzhydryl moiety, (e) branched tert-butyl or isopropyl
moiety, (f) piperazine and 4-aminopiperidine moiety, (g) 1,4-dihydropyridine moi-
ety, (h) tetrahydro isoquinolines, and (i) cyproheptadine derivatives. The general
observation of this diverse class of compounds showed commonly the lipophilic
character and the presence of single basic nitrogen in the structure [
1
].
Over the past few decades, a variety of in silico models for NCC blockers have
been developed by different research groups to improve selectivity and ADME/T
properties. Recently, we have developed robust 2D-QSAR model to determine the
biological activity of different scaffolds of 104 nonpeptidyl derivatives acting as
NCC blockers. The NCC blocking potency (IC
50
) values were measured under the
same experimental conditions using a fluorescence-based Ca
2+
flux assay in IMR32
human neuroblastoma cells [
71
].
2D-QSAR analysis was performed to explore the structure-activity relationship
of different scaffolds of nonpeptidyl derivatives acting as NCC blockers. These
blockers possess a variety of scaffolds (A, B, C, D, E and F), di-substituted with
different R and X groups and is presented in Fig.
2
.
Recently, genetic function algorithm (GFA) has gained great popularity in
QSAR research. In this study, GFA method developed by Rogers and Hopfinger
[
72
] was employed to select the relevant descriptors and to generate different
QSAR models. Sensitivity analysis on QSAR models was then performed, and
the best model developed can be used for predicting test set compounds that were
not included in the training set compounds.
C
A
B
O
O
H
N
N
R
R
N
H
N
N
H
R
N
N
O
O
OBz
OBz
X
D
E
F
O
H
N
O
X
R
O
N
H
N
X
N
N
H
R
N
X
N
O
R
1
O
O
OBz
OBn
Fig. 2 Six different scaffolds (A-F) of N-type Ca
2+
channel blockers (From [71]. With permis-
sion from Springer)
