QSAR attempts to find consistent relationships between biological activity and molecular properties using mathematical equations. Commonly studied molecular properties include lipophilicity, measured by log P values, and electronic effects, measured by Hammett constants. Hansch first applied QSAR by relating biological activity to log P and Hammett constants. Lipophilicity influences absorption and binding, while electronic effects impact reactivity. QSAR allows predicting new compounds' activities from prior data on similar molecules.

1. Prepared By :
MAHENDRA G S
M-Pharm,Pharmaceutical
Chemistry
JSSCP, MYSURU

2. Why QSAR?
The number of compounds required for synthesis in order
to place 10 different groups in 4 positions of benzene ring
is 104
Solution: synthesize a small number of compounds and
from their Physicochemical and Biological activity data
derive rules to predict the biological activity of other
compounds.

3. What is QSAR?
A quantitative structure-activity relationship
(QSAR) is a mathematical relationship which
correlates measurable or calculable molecular
properties to some specific biological activity in
terms of an equation
QSAR attempts to find consistent relationship
between biological activity and molecular
properties, so that these “rules” can be used to
evaluate the activity of new compounds.
• Understanding QSAR regarding electronic
effects, steric effects and lipophilicity.

4. QSAR and Drug Design
•To modify the chemical structure of the lead compound
to retain or to reinforce the desirable pharmacologic
effect while minimizing unwanted pharmacological and
physical and chemical properties, which may result in a
superior therapeutic agent;
•To use target analogs as pharmacological probes to
gain better insight into the pharmacology of the lead
molecule and perhaps to reveal new knowledge of basic
biology.

5. History
 1900, H. H. Meyer and C. E. Overton: lipoid theory of narcosis
 1930‘s, L. Hammett: electronic sigma constants
 1964, C. Hansch and T. Fujita: QSAR
 1984, P. Andrews: affinity contributions of functional groups
 1985, P. Goodford: GRID (hot spots at protein surface)
 1988, R. Cramer: 3D QSAR
 1992, H.-J. Böhm: LUDI interaction sites, docking, scoring
 1997, C. Lipinski: bioavailability rule of five
 1998, Ajay, W. P. Walters and M. A. Murcko; J. Sadowski and
H. Kubinyi: drug-like character Hugo Kubinyi,

6. Different models in QSAR
1.Free Energy Relationships
Hansch method : Linear Free Energy Relationships
(physicochemical properties)
Martin & Kubinyi : Non Linear Free Energy Relationships
(physicochemical properties)
Free Wilson mathematical model (structural elements)
2.Molecular Modeling
3.Quantum Mechanical Model
4.Topological Method
5.Pattern Recognization

7. Linear Free Energy Relationships
 Linear Free Energy Relationships allow a correlation of
substituents with a reaction rate, biological activity, pKa, etc.
 To help us understand the magnitude of the sensitivity of
parameter to changing substituents, with respect to a reference
reaction.
what Hammett accomplished
• To relate the biological activity of a series of
compounds to their physicochemical parameters in a
quantitative fashion using a mathematical formula

8. To relate the biological activity of a
series of compounds to their
physicochemical parameters in a
quantitative fashion using a
mathematical formula
Most common
properties studied

9. Lipophilicity and dissociation / ionization are responsible for
transport and distribution of drugs in biological systems.
The geometric fit and the complementarity of the surface 3D
properties of a ligand are responsible for its affinity to a binding site.

10. Hansch’s Approach
• The first application of QSAR is attributed to
Hansch (1969), who developed an equation
that related biological activity to certain
electronic characteristics and the
hydrophobicity of a set of structures

11. Log P
Log P is a measure of the drug’s hydrophobicity, which was selected
as a measure of its ability to pass through cell membranes.
The log P value reflects the relative solubility of the drug in octanol
(representing the lipid bilayer of a cell membrane) and water (the
fluid within the cell and in blood)
Log P = Log K (o/w) = Log ([X]octanol/[X]water)
Effect of varying log P & its affects the biological activity.
Biological activity normally expressed as 1/C, where C = conc. drug
required to achieve a defined level of biological activity. The more
active drugs require lower concentration.
Partition Coefficient P = [Drug in octanol]
[Drug in water]
High P High hydrophobicity

12. Example General anaesthetic activity of ethers
(parabolic curve - larger range of log P values)
Optimum value of log P for anaesthetic activity = log Po
Log
1
C




= - 0.22(logP)
2
+ 1.04 logP + 2.16
Hydrophobicity of the Molecule
Log P o
Log P
Log (1/C)

13. Hydrophobicity of Substituents
- the substituent hydrophobicity constant (p)
Notes:
•A measure of a substituent’s hydrophobicity relative to hydrogen
•Tabulated values exist for aliphatic and aromatic substituents
•Measured experimentally by comparison of log P values with log P of parent structure
Example:
•Positive values imply substituents are more hydrophobic than H
•Negative values imply substituents are less hydrophobic than H
Benzene
(Log P = 2.13)
Chlorobenzene
(Log P = 2.84)
Benzamide
(Log P = 0.64)
Cl CONH2
pCl = 0.71 pCONH = -1.492

14. Notes:
•The value of p is only valid for parent structures
•It is possible to calculate log P using p values
•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
Hydrophobicity of Substituents
- the substituent hydrophobicity constant (p)
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

15. Electronic Effects:
The Hammett Constant s
Hammett constant (1940) s
Measure e-withdrawing or e-donating effects (compared to
benzoic acid & how affected its ionization) The Hammett
substituent constant (s ) reflects the drug molecule’s intrinsic
reactivity, related to electronic factors caused by aryl substituents

16. Electronic Effects
Hammett Substituent Constant (s)
Notes:
•The constant (s) is a measure of the e-withdrawing or e-donating influence of
substituents
•It can be measured experimentally and tabulated
(e.g. s for aromatic substituents is measured by comparing the
dissociation constants of substituted benzoic acids with benzoic acid)
X=H K
H
= Dissociation constant =
[PhCO 2
-
]
[PhCO 2H]
+CO2H CO2 H
X X

17. +
X = electron
withdrawing
group
X
CO2CO2H
X
H
X= electron withdrawing group (e.g. NO2)
s X = log
K X
K H
= logK X - logK H
Charge is stabilised by X
Equilibrium shifts to right
KX > KH
Positive value
Hammett Substituent Constant (s)

18. X= electron donating group (e.g. CH3)
s X = log
K X
K H
= logK X - logK H
Charge destabilised
Equilibrium shifts to left
KX < KH
Negative value
Hammett Substituent Constant (s)
+
X = electron
withdrawing
group
X
CO2CO2H
X
H

19. Steric Factors
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
•Cannot be used for substituents which interact with the transition state by resonance or
hydrogen bonding
•May undervalue the steric effect of groups in an intermolecular process (i.e. a drug
binding to a receptor)

20. Aliphatic electronic substituents
•Defined by sI
•Purely inductive effects
•Obtained experimentally by measuring the rates of hydrolyses of aliphatic esters
•Hydrolysis rates measured under basic and acidic conditions
X= electron donating Rate sI = -ve
X= electron withdrawing Rate sI = +ve
Basic conditions: Rate affected by steric + electronic factors
Gives sI after correction for steric effect
Acidic conditions: Rate affected by steric factors only
+
Hydrolysis
HOMe
CH2 OMe
C
O
X CH2 OH
C
O
X

21. Steric Factors
Molar Refractivity (MR) - a measure of a substituent’s volume
MR =
(n 2
-1)
(n 2
- 2)
x
mol. wt.
density
Correction factor
for polarisation
(n=index of
refraction)
Defines volume

22. Thank you