Biomedical Engineering Reference
In-Depth Information
their clinical utility, Coi et al. [
67
] have carried out an exhaustive QSAR study on
the BK channel opening profile of several benzotriazole, benzimidazolone and
benzanilide derivatives sharing a large common sub-structure among them (12).
The minimum common hyper-structure space of these analogues is schematically
shown in 12. On this (hyper-structure template), R, R
1
and R
2
may be
functionalized alkyl and aryl moieties, and X is satisfied by CH, CO, N, or even
absent depending on the chemical class.
R
1
N
X
R
N
R
2
12
For all the compounds, the BK channel opening potency was measured in terms
of IC
50
, the concentration of the compound to evoke 50% reduction of the contrac-
tile tone induced by KCl 20 mM. Coi et al. [
67
] had derived the following QSAR
rationale for the activity of these compounds involving a heuristic procedure
available in CODESSA [
21
].
pIC
50
¼
33
:
700
0
:
216 Max
n
ð
n
repulsion for a C
N bond
Þ
þ
0
:
588 Kier flexibility index
ð
Þþ
11
:
500 Min atomic orbital electronic population
ð
Þ
þ
6
:
870 ZX Shadow
ð
=
ZXRectangle
Þþ
2
:
550 Average bond order of a O atom
ð
Þ
þ
75
:
300 Max valence of a H atom
ð
Þ
8
:
170 Max valence of a O atom
ð
Þ
þ
520
:
000 HACA
ð
2
=
TMSA
Þþ
31
:
400 Min partial charge for a C atom
ð
Þ
5
:
17 YZ Shadow
ð
=
YZRectangle
Þþ
29
:
500 Max partial charge for a H atom
ð
Þ
þ
0
:
033 ZX Shadow
ð
Þ
0
:
049 HACA
ð
1
Þ
r
2
Test
r
2
Q
2
n
¼
66
;
¼
0
:
73
;
¼
0
:
56
;
¼
0
:
91
:
(20)
The molecular features emerged in this model are from topological (Kier
flexibility index), geometrical (ZX Shadow/ZX Rectangle, YZ Shadow/YZ Rect-
angle and ZX Shadow), electrostatic (HACA-2/TMSA, minimum partial charge for
a C atom, and maximum partial charge for a H atom) and quantum-chemical
(maximum n-n repulsion for a C-N bond, minimum atomic orbital electronic
population, average bond order of a O atom, maximum valence of a H atom,
maximum valence of a O atom, and HACA-1) classes of CODESSA molecular
descriptors. Further information of these descriptors can be found from [
21
,
22
].
These descriptors provided some basis for improving the BK channel opening
activity of the compounds. This study showed how a diverse chemical space can
be unified into single scaffold space in explaining the biological response of all
compounds.
