Chemistry Reference
In-Depth Information
NO2
= log
P
nitrobenzene
- log
P
benzene
= 1.85 - 2.13 = - 0.28
(8)
The partition coefficient
P
is a measure of the overall hydrophobicity of the drug and is therefore an important
measure of how efficiently a drug is transported to its target site and bound to its receptor or enzyme. The factor
measures the hydrophobicity of a specific region on the skeleton of the drug. Thus, any hydrophobic bonding to a
receptor involving that region will be more significant to the equation than the overall transport process. If the
substituent is involved in hydrophobic bonding to a receptor or enzyme, then the QSAR equation using the factor
will emphasize that contribution to biological activity more dramatically than the equation using
P
.
STERIC FACTORS
The bulk, size, and shape of a drug may have an influence on the interaction with its receptor. Quantifying steric
properties is more difficult than quantifying hydrophobic or electronic properties. Attempts have been made to
quantify the steric features of subtituents by using Taft's steric factor (
E
S
). Taft in 1952 [11], as a modification to the
Hammett equation, used the relative rate constants of the acid-catalysed hydrolysis of -substituted methyl acetates
to define the steric parameter because it had been shown that the rates of these hydrolyses were almost entirely
dependent on steric factors. He used methyl acetate as his standard and defined
E
S
as:
E
s = log [
k
(XCH2COOR)
/
k
(CH3COOR)
]
(9)
where
k
is the rate constant of the appropriate hydrolysis and
E
S
= 0 when X = H. It is assumed that the values of
E
S
obtained for a group using the hydrolysis data are applicable to other structures containing that group. The methyl-
based
E
S
values can be converted to H-based values by adding -1.24 to the corresponding methyl-based values.
Molar refractivity (MR) is the chameleon amongst the physicochemical parameters, despite its broad application in
QSAR studies.
MR = MV · (
n
2
- 1)/(
n
2
+ 2)
(10)
where MV = molecular volume, and
n
= refractive index. MR is generally scaled by 0.1.
It has been correlated with lipophilicity, molar volume, and steric bulk. Of course, due to its MV component [MV =
MW/d (MW = molecular weight, d = density)], it is indeed related to volume and size of a substituent. The refractive
index-related correction term in MR accounts for the polarizability and thus for the size and the polarity of a certain
group [12, 13]. Since the refractive index
n
varies only slightly for most organic compounds, molar volume (MV) is
usually highly interrelated with MR. For other steric parameters and more detailed information, refer to topics and
chapters by Hansch and Leo, Silipo and Vittoria, and Franke [3, 14-16].
Another approach to measuring the steric factor involves a computer programme called sterimol which calculates
steric substituent values from standard bond angles, Van der Waals radii, bond lengths, and possible conformations
for the substituent.
HANSCH EQUATION
The third and most important contribution was to add several different physicochemical parameters, like
lipophilicity, electronic properties, and steric properties of substituents into one equation. These equations are
known as Hansch equations and they usually relate biological activity to the most commonly used physicochemical
properties [
P
and/or , , and a steric factor (
E
S
)]. If the hydrophobicity values are limited to a small range then the
equation will be linear, as follows [equation (11)]:
log (1/C) =
k
1
log
P
+
k
2
+
k
3
E
S
+
k
4
(11)
If the
P
values are spread over a large range, then the equation will be parabolic [equation 12)]:
log (1/C) = -
k
1
(log
P
)
2
+
k
2
log
P
+
k
3
+
k
4
E
S
+
k
5
(12)
