International Journal of Pharmaceutical Applications ISSN 0976-2639.

Vol 1, Issue 2, Dec-2010, pp 62-75 http://www.bipublication.com

QSAR-A NOVEL TOOL IN DRUG DESIGN

Shinde Mayuresh, Jangam Tukaram, Chougule Ujjawala,
Mahanthesh M.C., Bhatia Manish*
Department of Pharmaceutical Chemistry, Tatyasaheb Kore College of Pharmacy, Warananagar
*
Bharati Vidyapeeth College of Pharmacy and research center, Kolhapur
Abstract-:
Quantitative Structure-Activity Relationship (QSAR) techniques are used to develop correlations between
biological activity and physicochemical properties of a set of molecules. It describes the main parameters
used to quantify physicochemical properties in terms of the general concepts of electronic, steric and
hydrophobic effects. QSAR data is applied for the determination of stability, distribution, toxicity prediction
and lead optimization of drug candidates from structure-activity data. The results can be used to understand
interactions between functional groups in the molecules of greatest activity with those of their target. To do
this it is important to interpret any derived QSAR in terms of the fundamental chemistry of the set of
analogues, including any outliers.

Key Words-: QSAR, drug design, electronic effect, steric effect, hydrophobic effect, drug discovery

INTRODUCTION-: PARAMETER SYMBOL

Hydrophobic parameters
Advantages of QSAR1, 2, 3,4,5,6: Partition coefficient log P
1. Quantifying the relationship between Substituent constant
structure and activity provides an Hydrophobic fragmental constant f, f'
Distribution coefficient log D
understanding of the effect of structure on
Apparent partition coefficient
activity, which may not be straightforward log P', log Papp
(fixed pH)
when large amounts of data are generated. Capacity factor in HPLC log k, log kw
Solubility parameter log S
2. There is also the potential to make
Electronic descriptors
predictions leading to the synthesis of novel Hammett constants , -
, +

analogues. Interpolation is readily justified, Taft's inductive (polar) constants *, I

but great care must be taken not to use Swain and Lupton field parameter F
Swain and Lupton resonance
extrapolation outside the range of the data parameter
R

set. Ionization constant pKa , pKa

Chemical shifts (13C and 1H)
QSAR PARAMETERS:
Theoretical parameters
Physicochemical properties can be broadly Atomic net charge q ,q
classified into three general types: Superdelocazibility SN, SE, SR
1. Electronic Energy of highest occupied
E HOMO
molecular orbital
2. Steric
Energy of lowest unoccupied
E LUMO
3. Hydrophobic molecular orbital
For which an enormous range of properties Electrostatic potential V(r)
Steric descriptors
and physicochemical parameters have been Taft's steric parameter Es
defined. Ideally the parameters selected Molar volume MV
should be orthogonal and should have Molecular weight MW
Van der Waals radius r
minimal covariance.
Van der Waals volume Vw
1) HYDROPHOBIC PARAMETERS7, 8, 9, 10, Molar refractivity MR
11,12,13,14
: Parachor Pr
STERIMOL parameters L, Bi
Lipophilicity:
 QSAR-A NOVEL TOOL IN DRUG DESIGN

and use of theoretical correlations have

resulted in a large number of tabulated logP
and values. Typical values for for
different substituent are
Hydrophobic Hydrophilic
Substituent > 0 Substituent <0
-CH3 0.56 -NO2 -0.28
-C(CH3)3 1.98 -OH -0.67
-C6H5 1.96 -CO2H -0.32
-C6H11 2.51 -NH2 -1.23
-CF3 0.88 -CHO -0.65
Hydrophobic interaction between a drug
and a binding site at a receptor The usefulness of values is to estimate log P
Definition of Partition Coefficients of a substituted compound, given the logP of a
P = Corg/Caq (n-octanol/water system) parent molecule. For example,
Clearly absorption and distribution processes logPphenol = logPbenzene + OH =2.13 + (-0.67) =
in biological systems are determined by the 1.46
hydrophilic or hydrophobic properties of
molecules, for which the partition coefficient
of a molecule is used. P is defined by:
logPtoluene = logPbenzene + CH3 = 2.13 + (0.56)
= 2.69

By using a logarithmic relationship, P

becomes an additive property:

logPPABA = logPbenzene + CO2H + NH2 = 2.13

+ (-0.32) + (-1.23) = 0.58
The contribution of a substituent, X, to the
logP of a molecule is defined by

A large number of logP values have been

measured experimentally and tabulated in
Exploring QSAR and typical values are shown
below.
is the hydrophobic parameter for a
specific substituent. Extensive measurements

63
Shinde Mayuresh et al.
 QSAR-A NOVEL TOOL IN DRUG DESIGN

particularly at pH values far from that of the

Examples: neutral species of interest. Based on
Calculation of the log P Value of m- correlations between experimentally measured
Chlorotoluene and theoretical values, contributions to logP
log P = log P Benzene + π Cl + π Me have been calculated for molecular fragments,
= 2.13 + 0.71 + 0.56 = 3.40 enabling an estimate to be made for the logP
log P = log P Toluene + π meta-Cl of a molecule based on the structural formula.
= 2.69 + 0.76 = 3.45
log P = log P Chlorobenzene + π meta-Me
= 2.84 + 0.51 = 3.35
log P exp = 3.28
log P values are dependent on the
experimental method, as shown for the
recorded values for Phenobarbital,
C12H12N2O3 . Where a molecule possesses one For example, for Phenobarbital, a logP of 1.71
or more ionizable groups, each of which was estimated using the following fragmental
makes a contribution to the overall partition constants:
coefficient, then logD would need to be used
log P = 5(0.37) -0.08 -0.22 + 0.53 + 0.91 -2.65
-CH=(aryl) 0.37 -CH=(aryl*) -0.08
+ 2(0.35) + 0.67 = 1.71
>C<(*) -0.22 -CH2- 0.53
Note that the -C=O and -NH- fragments of the
-CH3 0.91 barbiturate -2.65
barbituric acid portion have a combined effect
Interactions between aliphatic and aryl 0.35
on logP when closely associated, as in these
systems:
molecules, that is different from their values Interactions within barbiturate system: 0.67
in isolation. As a result, barbituric acid has a Anticonvulsant activity of a diverse series of
calculated log P of -1.41. Similarly the starred drugs has been shown to be related to logP by
atoms (*) differ from normal sp3 and sp2 the equation:
atoms in their intermolecular interactions
depending on whether they are in barbituric
acid, or Phenobarbital, where extra effects
occur.

64
 QSAR-A NOVEL TOOL IN DRUG DESIGN

fat depots, thereby decreasing their

availability and activity.
Extension of the above study to include more
lipophilic molecules supports this, giving
overall a parabolic relationship. By
differentiation, this gives an optimum log P
This implies that anticonvulsant activity value of approximately 1.75, a value typical
would increase indefinitely by increasing the for most CNS-active drugs.
lipophilicity of the drugs. Clearly, however,
there must be a limit to this increase.
Lipophilic molecules could become trapped in

2) ELECTRONIC PARAMETERS
27,28,29,30,31,32,33,50,51,52,53
:
Electronic properties were initially developed
from a consideration of constituent effects in
aromatic compounds. For example, the
dissociation constants of substituted benzoic
acids
Where is the substituent constant for a given
group, R, and its position, and Ka are acid
dissociation constants. It is possible to have
o, m and p values. Typical values of the
substituent constants, m and p are shown in
the following table.
Substituent Meta Para Ortho
O -0.708 -1.00 F
CH OCH NO
R H F Cl OH +0.121 -0.37 Cl
3 3 2
orth 6.2 12. 54. 11. OCH3 +0.115 -0.268 CO2 H
8.06 671
o 7 3 1 4 NH2 -0.161 -0.660 COCH3
6.2 5.3 13. 14. 32. CH3 -0.069 -0.170 CF3
meta 8.17
7 5 6 8 1 (CH3)3Si -0.121 -0.072 SO2 Ph
6.2 4.2 7.2 10. 37. C6 H5 +0.06 -0.01 NO2
para 3.38 +
7 4 2 5 0 H 0.000 0.000 N(CH3)3
is transferable to many reactions involving
benzene and other aromatic species, leading to

65
 QSAR-A NOVEL TOOL IN DRUG DESIGN

a generalized form of the equation known as PABA, requires that they act in the anionic
the Hammett equation: form.

is the constant for a given reaction, is the

substituent constant, and Ka is the equilibrium
constant (or rate constant, ka) for the reaction
of interest. There are several other ways of
quantifying electronic effects. For example,
electronic effects can be represented as a
linear combination of a field (inductive)
effect, F, and a resonance effect, R:

The dissociation reaction of sulfanilamide

Where a and b are coefficients determined depends on the electronic properties of the
from data fitting. The use of has been substituent, R, which may stabilize the anion
extended to biological activity. by electron withdrawal, thus increasing
Examples: biological activity. The plots show the
The antibacterial activity of sulphanilamides, correlation between and pKa against
whose activity has been shown to depend on bacteriostatic activity for a series of 20 and 14
their similarity to the natural metabolite, sulfanilamide, respectively.

Hammett observed that adding substituents to

the aromatic ring of benzoic acid had an
orderly and quantitative effect on the
dissociation constant. For example,
Linear Free Energy Relationships
(Hammett equation) 26, 30:
Hammett correlated electronic properties of
organic acids and bases with their equilibrium
constants and reactivity. Consider the
dissociation of benzoic acid:
a nitro group in the meta position increases the
dissociation constant, because the nitro group
is electron-withdrawing, thereby stabilizing
the negative charge that develops. Consider
now the effect of a nitro group in the para
position.

66
 QSAR-A NOVEL TOOL IN DRUG DESIGN

indicating even greater electron-withdrawal.

The equilibrium constant is even larger than Now consider the case in which an ethyl
for the nitro group in the meta position, group is in the para position:

substituted compounds. Values for the

In this case, the dissociation constant is lower abscissa are calculated from the dissociation
than for the unsubstituted compound, constants of unsubstituted and substituted
indicating that the ethyl group is electron- benzoic acid. Values for the ordinate are
donating; thereby destabilizing the negative obtained from another organic acid or base
charge that arises upon dissociation. Hammett with identical patterns of substitution. Because
also observed that substituents have a similar this relationship is linear, the following
effect on the dissociation of other organic equation can be written:
acids and bases. Consider the dissociation of
phenyl acetic acids:

the slope of the line is a proportionality

constant pertaining to a given equilibrium.
is a descriptor of the substituent. The
magnitudes of gives the relative strength of
the electron-withdrawing or donating
properties of the constituents. is positive if
the substituent is electron-withdrawing and
negative if it is electron-donating.
These relationships as developed by Hammett
Electron-withdrawal by the nitro group are termed linear free energy relationships.
increases dissociation, with the effect being Recall the equation relating free energy to
less for the meta than for the para substituent, equilibrium constant:
just as was observed with benzoic acid. The
electron-donating ethyl group decreases the That is, the free energy is proportional to the
equilibrium constant, as would be expected. logarithm of the equilibrium constant. These
Data for these equilibria typically are graphed linear free energy relationships are termed
as illustrated below: "extra thermodynamic". Although they can be
stated in terms of thermodynamic parameters,
no thermodynamic principle states that the
relationships should be true. To develop a
better understanding of these relationships, it
is instructive to consider some values of
and . Values of are provided below:
K0 or K0` represents equilibrium constants for
unsubstituted compounds and K or K' for

67
 QSAR-A NOVEL TOOL IN DRUG DESIGN

electronegativity of the constituent atoms. If

only induction were operative, one would
expect the electron-withdrawing effect of a
nitro group in the para position to be less than
in the meta position. The larger value for a
para-substituted nitro group results from the
combination of both inductive and resonance
effects. For chlorine, the electronegativity of
In the aniline and phenol equilibria, the the atom produces an inductive electron-
hydrogen ion that is dissociating is one atom withdrawing effect, with the magnitude of the
removed from the phenyl ring, whereas in the effect in the para position being less than in
benzoic acid equilibrium it is two atoms the meta position. For chlorine, only the
removed. Thus, substituents are able to exert a inductive effect is possible. The methoxy
greater effect on the dissociation in aniline group can be electron-donating or -
and phenol than in benzoic acid and the value withdrawing, depending on the position of
of > 1. In phenyl acetic and phenyl substitution. In the meta position, the electro
propionic acids, the hydrogen ion dissociating negativity of the oxygen produces an
is three and four atoms removed, respectively, inductive electron-withdrawing effect. In the
from the phenyl ring. Substituents are able to para position, only a small inductive effect
exert a lesser effect on the equilibrium than on would be expected. Moreover, an electron-
the benzoic acid equilibrium and < 1.Some donating resonance effect occurs for the
illustrative values of for substituents in the methoxy group in the para position, giving an
meta and para positions are given below: overall electron-donating effect. Tables of
values for numerous substituents have been
published. In some cases, the sigma values are
generally applicable to many different
equilibrias. In other cases, sigma values have
been derived for specific equilibria, which is
particularly true when one considers sigma
values for ortho substituent.
3) STERIC PARAMETERS :
i. Taft’s steric parameter (Es)
By definition, for hydrogen is 0. The 15,16,17,18,19,20,21,22,23,24,25,26
:
positive values of for the nitro group
indicate that it is electron-withdrawing. In Taft quantified the steric (spatial) effects using
understanding the magnitudes of the values the hydrolysis of esters15:
for the nitro group in meta vs. para positions,
consider the mechanisms of electron
withdrawal or donation. For a nitro group in
the meta position, electron-withdrawal is due Here, the size of R affects the rate of reaction
to an inductive effect produced by the by blocking nucleophilic attack by water.

68
 QSAR-A NOVEL TOOL IN DRUG DESIGN

In this case, the steric effects were quantified

by the Taft parameter Es:

Organophosphates must be hydrolyzed to be

active and it is observed that their biological
activity is directly related to the Taft steric
k is the rate constant for ester hydrolysis. This parameter E S for the substituent R by the
expression is analogous to the Hammett equation:
equation.
Typical Es values are:
Es Values for Other steric parameters used include
Various Substituent STERIMOL size parameters and molar
refractivity.
H M Pr t- F Cl Br O S N C6 C N
e Bu H H O2 H5 N H2
ii. Verloop Steric Parameter
0. - - - - - - - - - - - - (STERIMOL)23 :-
0 1. 1. 2. 0. 0. 1. 0. 1. 2. 3.8 0. 0. STERIMOL size parameters (L, B1, B2, B3 and
24 60 78 46 97 16 55 07 52 2 51 61 B4) proposed by Verloop, are dimensions of
the substituent, R, defined as:
Note: H is usually used as the reference L = length along the axis of the bond joining
substituent (Es0), but sometimes when another R to the parent molecule
group, such as methyl (Me) is used as the Bi = the four width parameters, at right angles
reference, as in the chemical equation above, to the axis, L, viewed in cross-section,
the value becomes 1.24. As was the case for and B1 < B2 < B3 < B4. (Hint: Imagine a
, Es may be used in other chemical reactions substituent enclosed in a rectangular box)
and to explain biological activities, for
example the hydrolysis of inhibitors of
acetylcholine esterase.
Values of STERIMOL Parameters for Various Substituents
Substituents H Me n-Pr t-Bu F Cl Br OH SH NO2 C6 H5 CN NH2
L 2.06 3.00 5.05 4.11 2.65 3.52 3.83 2.74 3.47 3.44 6.28 4.23 2.93
B1 1.00 1.52 1.52 2.59 1.35 1.80 1.95 1.35 1.70 1.70 1.70 1.60 1.50
B2 1.00 2.04 3.49 2.97 1.35 1.80 1.95 1.93 2.33 1.70 1.70 1.60 1.50
B3 1.00 1.90 1.90 2.86 1.35 1.80 1.95 1.35 1.70 2.44 3.11 1.60 1.84
B4 1.00 1.90 1.90 2.86 1.35 1.80 1.95 1.35 1.70 2.44 3.11 1.60 1.84

69
 QSAR-A NOVEL TOOL IN DRUG DESIGN

iii. Molar Refractivity16: initially. Thus, an optimum hydrophobicity

may be found in some test systems. QSAR are
Where n is the refractive now developed using a variety of parameters
index, MV= MW/d is the as descriptors of the structural properties of
molar volume, MW = molecular weight and d molecules. Hammett’s
= density. MR is a combination of volume sigma values are often used for electronic
(MV) and polarizability (a property of n) in a parameters, but quantum mechanically
molecule, and has been used successfully in derived electronic parameters also may be
many QSAR studies. used. Other descriptors to account for the
OTHER QSAR METHODS shape, size, lipophilicity, polarizability, and
Hansch method20, 22, 33, 34, 35, 36:- other structural properties also have been
QSAR based on Hammett's relationship devised.
utilize electronic properties as the descriptors Free Wilson analysis 17, 20, 26, 28, 36:-
of structures. Difficulties were encountered The Free-Wilson approach is truly a structure
when investigators attempted to apply activity- based methodology because it
Hammett-type relationships to biological incorporates the contributions made by
systems, indicating that other structural various structural fragments to the overall
descriptors were necessary. Relationships biological activity. It is represented by
were developed to correlate a structural equation
parameter (i.e., lipophilicity) with activity. In BA i = ∑ aj Xi j + µ
some cases, a univariate relationship Indicator variables are used to denote the
correlating structure and activity was presence or absence of a particular structure
adequate. The form of the equation is: feature. Like classical QSAR, this de novo
approach assumes that substituent effects are
additive and constant. BA is the biological
Where C is the molar concentration of activity; Xj is the j th substituent, which
compound that produces a standard response carries a value 1 if present, 0 if absent. The
(e.g., LD50, ED50). With other data, it was term aj represents the contribution of the j th
observed that correlations were improved by substituent to biological activity and µ is the
combining Hammett's electronic parameters overall average activity. The summation of all
and Hansch equation to measure the activity contributions at each position must
lipophilicity using an equation such as equal zero. The series of linear equations that
are formulated are solved by linear regression
analysis. It is necessary for each substituent to
Where is the Hammett substituent appear more than once at a position in
parameter and pi is defined analogously to . different combinations with substituent at
That is, other positions.
Free and Wilson reasoned that the biological
activity for a set of analogues could be
In yet other cases, parabolic relationships described by the contributions that substituent
between biological response and hydrophobic or structural elements make to the activity of a
parameters were observed that could be fit by parent structure. Free-Wilson equations do not
including a (log P) **2 term in the QSAR. require the use of substituent constants such as
One interpretation to account for this term is , m, p, F, R, ES, and MR, and are
that many membranes must be traversed for represented by the general equation:
compounds to get to the target site, and those
with greatest hydrophobicity will become
localized in the membranes they encounter

70
 QSAR-A NOVEL TOOL IN DRUG DESIGN

Where aj is the group contribution of the combination of Free-Wilson analysis and

structural feature X in position j in molecule i Hansch analysis. The indicator variables can
and is the theoretical biological activity be used to describe a variety of structural
value of a reference or parent compound. The features, such as substructures, chiral centers
descriptor Xij has a value of 1 if the feature is and special substituents.
present in position j in molecule i and 0 in the A typical tabulation for a set of compounds is
absence of that feature. There are advantages shown in the following table:
and disadvantages of Free-Wilson type
analyses that are discussed in Exploring
QSAR.
The presence and absence of structural
elements is indicated by the values 1 and 0,
respectively. It is possible to add indicator
variables to the Hansch equation as a
log
Meta Para Meta- Para- log 1/C
1/C
(X) (Y) F Cl Br I Me F Cl Br I Me obsd. calc.a)
H H 7.46 7.82
H F 1 8.16 8.16
H Cl 1 8.68 8.59
H Br 1 8.89 8.84
H I 1 9.25 9.25
H Me 1 9.30 9.08
F H 1 7.52 7.52
Cl H 1 8.16 8.03
Br H 1 8.30 8.26
I H 1 8.40 8.40
Me H 1 8.46 8.28
Cl F 1 1 8.19 8.37
Br F 1 1 8.57 8.60
Me F 1 1 8.82 8.62
Cl Cl 1 1 8.89 8.80
Br Cl 1 1 8.92 9.02
Me Cl 1 1 8.96 9.04
Cl Br 1 1 9.00 9.05
Br Br 1 1 9.35 9.28
Me Br 1 1 9.22 9.30
Me Me 1 1 9.30 9.53
Br Me 1 1 9.52 9.51

71
 QSAR-A NOVEL TOOL IN DRUG DESIGN

MLR can be performed on data in the above

table, resulting in the regression equation that
follows. Notice that the independent variables
are the various groups shown in square
brackets and are simply indicates the status of
those groups. A negative coefficient indicates
that the presence of that group is unfavorable
to activity; a positive coefficient indicates that
the presence of that group is favorable to
activity.

An example of how substituent may be chosen

to give a spread of property space is given by
the following Craig plot, for and , but note
Multiple linear regressions17, 20, 26, 28, 37, 38, 39,
that any pair of physicochemical properties 40
:-
could be similarly displayed.
Hansch is recognized as having first
introduced MLR into QSAR in the form of the
Craig plot 19, 41, 42, 43, 44, 45, 46, 47, 48, 49 : -
following Hansch equation:
It is a plot of two substituent parameters (e.g.,
log (1/C) = a (log P)2 + b (log P) + c + d ES+
Hansch-Fujita and Hammett values) used
e +.....
in analog design.
Where a-e are constants determined for a
particular reaction or biological activity by
regression analysis. log P, , , F, R, ES etc,
are independent variables whose values are
obtained directly from experiment. More
general equations than the above form of the
Hansch equation can be derived which explore
all combinations of independent variables
using techniques such as backward or forward
stepping to determine the variables that give
an optimum explanation of the data .If there
are n independent variables to be considered,
then there are 2n-1 combinations of these
variables that may be used to best explain the
tabulated data, without considering higher
order terms. It is important to make sure that
the variables do not overlap in what they
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