Quantitative Structure Activity

Relationships (QSAR)
QSAR

QSAR approach attempts to identify and quantify the

physicochemical properties of a drug and to see whether any of
these properties has an effect on the drug’s biological activity by
using a mathematical equation

PHYSICOCHEMICAL PROPERTIES

 Hydrophobicity of the molecule

 Hydrophobicity of substituents
 Electronic properties of substituents
 Steric properties of substituents
 A range of compounds is synthesized in order to vary one
physicochemical property and to test it affects the bioactivity.

 A graph is then drawn to plot the biological activity on the

y axis versus the physicochemical feature on the x axis.

 It is necessary to draw the best possible line through the

data points on the graph. This done by procedure known as
linear regression analysis by the least square method.
 If we draw a line through a set of data points will be
scattered on either side of the line. The best line will be the
one closest to the data points.

 To measure how close the data points are , vertical lines

are drawn from each point.

Log (1/C)
. ..
. .. .. .
0.78 3.82 Log
P
HYDROPHOBICITY

Hydrophobic character of a drug is crucial to how easily it

crosses the cell membrane and may also important in receptor
interactions.

Hydrophobicity of a drug is measured experimentally by

testing the drugs relative distribution in octanol water mixture.
This relative distribution is known as partition coefficient.

Partition Coefficient P = conc. Drug in in octanol]

[Conc.of drug in water]
 Activity of drugs is often related to P

Biological activity log(1/c) = K1 log P + K2

Eg: binding of a drug to serum albumin determined by

hydrophobicity and study of 42 compounds.
(straight line - limited range of log P)

Log (1/C)

. . .
.
.. . . .
0.78 3.82 Log
P
 If the partition coefficient is the only
factor influencing biological activity, the
parabolic curve can expressed by the
equation

Log (1/C)
log(1/c) = -K1 (log P)2 + K2 log P + k3

Few drugs where activity is related to

log P factor alone.
Log P Log
 QSAR equations are only applicable to
o
P
compounds in the same structural class
(e.g. ethers)

 However, log Po is similar for

anaesthetics of different structural
classes
THE SUBSTITUENT HYDROPHOBICITY CONSTANT (π)

Partition coefficient can be calculated by knowing the

contribution that various substituents, is known as substituent
hydrophobicity constant(π)

 A measure of a substituent’s hydrophobicity relative to hydrogen

 Partition coefficient is measured experimently for a standard

compound such as benzene with or without a substituent (X).

 The hydrophobicity constant (π x) for sustituent X.

The equation is
x= logPx-logPH
 A possitive  value shows that the substituent is more
hydrophobic than hydrogen

A negative value indicates that the substituent is less

hydrophobic.
The  value is charecteristic for sustituent.

Example:

Cl = CONH2 = -
0.71 1.49
 THE SUBSTITUENT HYDROPHOBICITY CONSTANT (π)

Cl
Log P(theory) = log P(benzene) +   
2
O
     
NH2  
m e t a c h lo ro b e n za m id

 A QSAR equation may include both P and π.

 P measures the importance of a molecule’s overall hydrophobicity
(relevant to absorption, binding etc)

π identifies specific regions of the molecule which might interact

with hydrophobic regions in the binding site
ELECTRONIC EFFECT

The electronic effect of various sustituents will clearly have

an effect on drug ionisation and polarity.

Have an effect on how easily a drug can pass through the cell
membrane or how strongly it can interact with a binding site.

Hammet substituent constant(σ) this is a measure of electron

with-drawing or electron-donating ability of a substituents on an
aromatic ring.
 o for aromatic substituents is measured by comparing the
dissociation constants of substituted benzoic acids.

+
COOH COO + - H

[PhCO2-]
K H = Dissociation = [PhCO
constant
2H]
 X= electron withdrawing group (e.g. NO2,)

X = electron
withdrawing X X
group CO2H CO2 + H

Charge is stabilised by X
Equilibrium shifts to
right KX > KH

 X = log K = X - H
X
K log logK
H
K
Positive value
X= electron donating group (e.g. CH3)

X X +
COOH COO- + H

Charge destabilised
Equilibrium shifts to
left KX < KH

 = log K X = logK X - logK

X
H
KH
Negative value
 EXAMPL  p (NO2)   m (NO2) 
ES:  
meta-Substitution
O

N
O
e-withdrawing (inductive effect only)
DRUG

para-Substitution

O O O O O O O O
N N N N

e-withdrawing
(inductive +
resonance effects)
DRUG DRUG DRUG DRUG
o value depends on inductive and resonance effects

o value depends on whether the substituent is meta or para

ortho values are invalid due to steric factors

Electronic Factors R & F

 R - Quantifies a substituent’s resonance effects

 F - Quantifies a substituent’s inductive effects

The constants σ,R and F can only be used for aromatic substituents
Aliphatic electronic substituents

 Obtained experimentally by measuring the rates of hydrolyses

of aliphatic esters
 Purely inductive effects
 given by σI
 Hydrolysis rates measured under basic and acidic conditions
O O
Hydrolysis
C C + HOM e
X CH2 OMe X CH2 OH

X= electron donating Rate I = -ve

X= electron withdrawing Rate I =
+ve
STERIC FACTORS

The bulk, size and shape of a drug will influence how easily it can
approach and interact with binding site.

A bulky substituents may act like a shield and hinder the ideal
interaction between a drug and its binding site.

Bulky substituent may help to orient a drug properly for

maximum binding and increase activity.
Taft’s Steric Factor (Es)
 Measured by comparing the rates of hydrolysis of substituted
aliphatic esters against a standard ester under acidic conditions
Es = log kx - log ko

kx represents the rate of

hydrolysis of a substituted ester
ko represents the rate of hydrolysis of the parent ester

 Limited to substituents which interact sterically with the

tetrahedral transition state for the reaction
 Not by resonance or hydrogen bonding

Disadvantages

ES value measures intramolecular steric effect but drugs interact

with target binding site in intermolecular process (i.e. a drug
Verloop Steric
Parameter
- calculated by software (STERIMOL)
- gives dimensions of a substituent from the standard
bond angle ,van der Waals radii, bond length and possible
conformations for the substituents
- can be used for any substituent
Example - Carboxylic acid

B B
4 3
O B
3

B2
C
B1
O H O C O
B
4

L
 HANSCH EQUATION

 A QSAR equation relating various physicochemical

properties to the biological activity of a series of compounds

 Usually includes log P, electronic and steric factors

 Start with simple equations and elaborate as more structures

are synthesised

 Typical equation for a wide range of log P is parabolic


Lo 1  2
- k1(logP) + k 2 logP + k 3  + k 4 + k5
 C
g Es
Craig Plot
Craig plot shows values for 2 different physicochemical
properties for various substituents

. + 1.0

. . .
CF 3 SO 2

. . . . .
.75
NO2

.
CN SF5

..
.50

.
SO2 NH2 CH 3SO 2
CF3

.
CH 3 CO
CONH2

.
OCF3
.25

. . . .
CO2 H Cl Br I

-2.0 -.8 -.4 .4 .8 1.2 1.6 2.0

-1.6 -1.2 F

-
. . CH 3 CONH

OCH3
-.25 Me Et
t-B utyl
+


. NH2
. OH
-.50

NMe2
-.75

-1.0

-
 Allows an easy identification of suitable substituents for
a QSAR analysis which includes both relevant
properties

 Choose a substituent from each quadrant to ensure

orthogonality

 Choose substituents with a range of values for each

property