QSAR

By
Nehla p
Department of Pharmaceutical Chemistry
Grace college of pharmacy
QUANTITATIVE STRUCTURE
ACTIVITY RELATIONSHIP
 It is said to be a mathematical relationship in the form
of an equation between the biological activity and
measurable physiochemical parameters.

 QSAR attempts to identify and quantify the

physicochemical properties of a drug and to see
whether any of these property has an effect on the
drugs biological activity
• The parameters used in QSAR is a measure of
the potential contribution of its group to a
particular property of the parent drug.

• Activity is expressed as log(1/C).

C is the minimum concentration required to
cause a defined biological response.

Physicochemical property as log p..

 PARAMETERS
Various parameters used in QSAR studies are
‰

1.Lipophilic parameters: partition coefficient,

π- substitution constant.

2.Electronic parameters: Hammet constant,

dipole moment.

3.Steric parameters: Taft’s constant, molar

refractivity, Verloop steric parameter.
 LIPOPHILIC PARAMETERS
Lipophilicity is partitioning of the compound
between an aqueous and non-aqueous phase.

Partition coefficient:
P=[drug] in octanol/[drug] in water

High P High hydrophobicity

 Linear relationship between Log p and
Log 1/C

•Activity of drugs is often related to P

e.g. binding of drugs to serum albumin
(straight line - limited range of log P)

Log (1/C)

. . .
.
.. . . . Log1C = k1 logP + k2

0.78 3.82 Log P

•Binding increases as log P increases

•Binding is greater for hydrophobic drugs
 Non –linear relationship
between Log P and Log 1/C
Example 2 General anaesthetic activity of ethers
(parabolic curve - larger range of log P values)

Log (1/C)
1
Log C = - k1 (logP) 2 + k2logP + k3

o
Log P Log P

Optimum value of log P for anaesthetic activity = log Po

π-substituent constant or hydrophobic
substituent constants:
• The π-substituent constant defined by Hansch
and co-workers.
• Measure of how hydrophobic a substituent
is,relative to H
πx= log Px-log PH
Cl CONH2

Benzene Chlorobenzene Benzamide

(Log P = 2.13) (Log P = 2.84) (Log P = 0.64)

pCl = 0.71 pCONH 2 = -1.49

 •Positive values imply substituents are more hydrophobic than H
•Negative values imply substituents are less hydrophobic than H

Example : Cl
Log P(theory) = log P(benzene) + pCl + pCONH2
= 2.13 + 0.71 - 1.49
= 1.35
CONH2
Log P (observed) = 1.51

meta-Chlorobenzamide

•A QSAR equation may include both P and p.

•P measures the importance of a molecule’s overall hydrophobicity

(relevant to absorption, binding etc.)

• p identifies specific regions of the molecule which might interact with

hydrophobic regions in the binding site
 ELECTRONIC PARAMETERS
Hammett Substituent Constant (s)

Eg. 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

s X = log KX = logKX - logKH Positive value

KH
 X= electron donating group (e.g. CH3)

X = electron
withdrawing X X
group CO2H CO2 + H

Charge destabilised
Equilibrium shifts to left KX < KH

s X = log KX = logKX - logKH

KH Negative value
s value depends on inductive and resonance effects

s value depends on whether the substituent is meta

or para

ortho values are invalid due to steric factors

 Hammett Substituent Constant (s)

EXAMPLES: sp (NO2) =0.78 sm (NO2) =0.71

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
 Hammett Substituent Constant (s)

EXAMPLES: sm (OH) =0.12 sp (OH) =-0.37

meta-Substitution

OH

e-withdrawing (inductive effect only)

DRUG

para-Substitution

OH OH OH OH

e-donating by resonance
more important than
inductive effect
DRUG DRUG DRUG DRUG
 STERIC SUBSTITUTION CONSTANT
It is a measure of the bulkiness of the group it
represents and it effects on the closeness of contact
between the drug and receptor site. It is much harder
to quantitate.

 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
 Molar refractivity (MR)--measure of the volume
occupied by an atom or group--equation includes
the MW, density(d), and the index of
refraction(n)–
MR=(n²-1)MW/(n²+2)d

 Verloop steric parameter--computer program

uses bond angles, van der Waals radii, bond
lengths
 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

Log1C = - k1(logP)2 + k 2 logP + k 3 s + k 4 Es + k 5

Example: Adrenergic blocking activity of b-halo-b-arylamines
Y X

CH CH2 NRR'

1 

Log C = 1.22 p - 1.59 s + 7.89


Conclusions:
• Activity increases if p is +ve (i.e. hydrophobic substituents)
• Activity increases if s is negative (i.e. e-donating substituents)
 Free-Wilson Approach
Method

• The biological activity of the parent structure is measured

and compared with the activity of analogues bearing
different substituents
• An equation is derived relating biological activity to the
presence or absence of particular substituents
Activity = k1X1 + k2X2 +.…knXn + Z

• Xn is an indicator variable which is given the value 0 or 1

depending on whether the substituent (n) is present or not
• The contribution of each substituent (n) to activity is
determined by the value of kn
• Z is a constant representing the overall activity of the
structures studied
Advantages

• No need for physicochemical constants or tables

• Useful for structures with unusual substituents
• Useful for quantifying the biological effects of molecular
features that cannot be quantified or tabulated by the
Hansch method
Disadvantages

• A large number of analogues need to be synthesised to

represent each different substituent and each different
position of a substituent
• It is difficult to rationalise why specific substituents are
good or bad for activity
QSAR Software

Tripos – CoMFA, COMSIA

VolSurf
MSI – Catalyst, Serius

Docking Software

DOCK – Kuntz
Flex – Lengauer
LigandFit – MSI Catalyst
COMPARITIVE MOLECULAR FIELD
ANALYSIS
CoMFA involves placing of molecules in a grid and to
correlate field properties of the molecules with
biological activities.
Dick Crammer in 1988
Steps
1. Group of compounds having a common
pharmacophore is selected .
2. The 3-dimensional structures of reasonable
conformation must be generated from 2-dimensional
structures.

22
CoMFA

3.The energy minimized structures are fitted to

each other using pharmacophore
hypothesis.
4.Molecules are then aligned using active analog
approach, distance geometry method

23
 PHARMACOPHORE SELECTION
CO2 H

CH3
+ H +
d1 PD
NH d1 NH
PD
CH3
L H L
d2 d3 HO d2 d3
N
D
H D
OH

d1 PD
L L-LIPOPHILIC SITE
d2 d3
D-H- BOND DONOR
D
PD-PROTONATED H-
PHARMACOPHORE BOND DONOR

24
Identification Of Pharmacophore

OH

HO NHCH3

Build 3D
HO
model
Active conformation Define pharmacophore

25
CoMFA ALIGNMENT
MeO d3 OMe
OH LA BL

L d1 C
L1 d2
d3 D
d3 L
d2 Cl Cl
LA B Cl
C
L7 d2
HO d1 L
d1 L

"Pharmacophore"
L
C
OH
OH O L d3
d3 B d2
NMe2
L
A d2 C
L1
L
A d1 B
d1 CL7
HO O HO O

26
CoMFA
5. Once molecules are aligned, a grid or lattice is
established which surrounds the sets of analogues in
potential receptor space.

27
 CoMFA
•Place the pharmacophore into a lattice of grid points

Grid points

•Each grid point defines a point in space

28
 CoMFA
•Position molecule to match the pharmacophore

Grid points

•Each grid point defines a point in space

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CoMFA
 A Probe atom is placed at each grid point. Steric
and electrostatic fields are calculated for each
molecule in every grid point.
 Next step in a CoMFA is a partial least square
analysis to determine a minimal set of grid points
necessary to explain measured biological activities
of the compounds.
 CoMFA results are often presented in a graphical
form ;with contours :favorable and unfavorable
regions of different fields.

30
•A probe atom is placed at each grid point in turn

.
. Probe atom
. .
.

•Measure the steric or electrostatic interaction of the probe atom

with the molecule at each grid point 31
VOLSURF
The VolSurf program predicts a variety of ADME
properties based on pre-calculated models. The models
included are:
 drug solubility
 Caco-2 cell absorption
 blood-brain barrier permeation
 distribution
VOLSURF
VolSurf reads or computes molecular fields, translates
them to simple molecular descriptors by image
processing techniques.
These descriptors quantitatively characterize size,
shape, polarity, and hydrophobicity of molecules, and
the balance between them.
VOLSURF

hydrophobic (blue) and hydrophilic (red) surface

area of diazepam.
 Catalyst
Catalyst develops 3D models (pharmacophores) from
a collection of molecules possessing a range of diversity
in both structures and activities.
Catalyst specifies hypotheses in terms of chemical
features that are likely to be important for binding to the
active site.
Each feature consists of four parts:
Chemical function
Location and orientation in 3D space
Tolerance in location
Weight
 substrates
pharmacophore

Hydrophobic area, h-bond donor, 2 h- Saquinavir (most active compound) fitted to

bond acceptors pharmacophore
3 D QSAR
 In 3 D QSAR, 3D properties of a molecule are considered as
whole rather than considering individual substituents.
 3D-QSAR involve the analysis of the quantitative
relationship between the biological activity of a set of
compounds and their three-dimensional properties using
statistical correlation methods.
 3 D QSAR revolves around the important features of a
molecule, its overall size and shape, and its electronic
properties.
•Physical properties are measured for the molecule as a whole
•Properties are calculated using computer software
•No experimental constants or measurements are involved
•Properties are known as ‘Fields’
•Steric field - defines the size and shape of the molecule
•Electrostatic field - defines electron rich/poor regions of
molecule
•Hydrophobic properties are relatively unimportant