QSAR IN CHEMISTRY

1. QSAR
By
Nehla p
Department of Pharmaceutical Chemistry
Grace college of pharmacy

2. 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

3. • 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..

4. 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.

5. 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

6. 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 P
. .
.
.. .
. ..
0.78 3.82
•Binding increases as log P increases
•Binding is greater for hydrophobic drugs
Log 1
C



= k1 logP + k2

7. 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 P
o
Log P
Log (1/C)
Optimum value of log P for anaesthetic activity = log Po
Log
1
C



= -k1 (logP) 2 + k2logP + k3

8. 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
Benzene
(LogP = 2.13)
Chlorobenzene
(Log P = 2.84)
Benzamide
(LogP = 0.64)
Cl CONH2
pCl = 0.71 pCONH = -1.492

9. •Positive values imply substituents are more hydrophobic than H
•Negative values imply substituents are less hydrophobic than H
Example :
meta-Chlorobenzamide
Cl
CONH2
Log P(theory) = log P(benzene) + pCl + pCONH
= 2.13 + 0.71 - 1.49
= 1.35
Log P (observed) = 1.51
2
•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

10. ELECTRONIC PARAMETERS
Hammett Substituent Constant (s)
Eg. X= electron withdrawing group (e.g. NO2)
+
X = electron
withdrawing
group
X
CO2CO2H
X
H
Charge is stabilised by X
Equilibrium shifts to right KX > KH
s X = log
KX
KH
= logKX - logKH Positive value

11. X= electron donating group (e.g. CH3)
+
X = electron
withdrawing
group
X
CO2CO2H
X
H
Charge destabilised
Equilibrium shifts to left KX < KH
s X = log
KX
KH
= logKX - logKH Negative value

12. 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

13. DRUG
N
O
O
meta-Substitution
EXAMPLES: sp (NO2) =0.78 sm (NO2) =0.71
e-withdrawing (inductive effect only)
e-withdrawing
(inductive +
resonance effects)
Hammett Substituent Constant (s)
N
O O
DRUG DRUG
N
OO
N
O O
DRUG DRUG
N
OO
para-Substitution

14. sm (OH) =0.12 sp (OH) =-0.37
e-withdrawing (inductive effect only)
e-donating by resonance
more important than
inductive effect
Hammett Substituent Constant (s)
EXAMPLES:
DRUG
OH
meta-Substitution
DRUG
OH
DRUG DRUG
OH OH
DRUG
OH
para-Substitution

15. 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

16.  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

17. 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 1
C



= -k (logP)2 + k2 logP + k3 s + k4 Es + k51

18. Log
1
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)
Example: Adrenergic blocking activity of b-halo-b-arylamines
CH CH2 NRR'
XY

19. Free-Wilson Approach
• 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
Method

20. • 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
Advantages
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

21. QSAR Software
Tripos – CoMFA, COMSIA
VolSurf
MSI – Catalyst, Serius
Docking Software
DOCK – Kuntz
Flex – Lengauer
LigandFit – MSI Catalyst

22. 22
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.

23. 23
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

24. 24
PHARMACOPHORE SELECTION
NH
+
CO2
H
CH3
H
N
H
L
PD
D
d1
d2 d3
NH
+H
CH3
OH
OH
L
PD
D
d1
d2 d3
L
PD
D
d1
d2 d3
PHARMACOPHORE
L-LIPOPHILIC SITE
D-H- BOND DONOR
PD-PROTONATED H-
BOND DONOR

25. 25
Identification Of Pharmacophore
NHCH3
OH
HO
HO
Active conformation
Build 3D
model
Define pharmacophore

26. 26
CoMFAALIGNMENT
C7
OH
OH
A
D
B
C1
MeO OMe
ClCl
Cl
BA
O
O
C7
OH
OH
OH
A
B
C1
O
NMe2
OH
A B
CL
L
L d1
d2
d3L
L
L
d1
d2
d3
L
L
L
d1
d2
d3
L
L
L
d1 d2
d3
L
L
L
d1
d2
d3
"Pharmacophore"

27. 27
CoMFA
5. Once molecules are aligned, a grid or lattice is
established which surrounds the sets of analogues in
potential receptor space.

28. 28
•Each grid point defines a point in space
•Place the pharmacophore into a lattice of grid points
•Each grid point defines a point in space
Grid points
CoMFA

29. 29
CoMFA
•Each grid point defines a point in space
Grid points
•Position molecule to match the pharmacophore

30. 30
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.

31. 31
•A probe atom is placed at each grid point in turn
•Measure the steric or electrostatic interaction of the probe atom
with the molecule at each grid point
.
.
.
.
.
Probe atom

32. 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

33. 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.

34. VOLSURF
hydrophobic (blue) and hydrophilic (red) surface
area of diazepam.

35. 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

36. substrates
pharmacophore
Hydrophobic area, h-bond donor, 2 h-
bond acceptors
Saquinavir (most active compound) fitted to
pharmacophore

37. 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.

38. •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