QSAR in medicinal chemistry

1. QSAR

2. INTRODUCTION
Principles of drug designing
• Improving the selectivity
• Increasing the selectivity
• Reduce side effects
• Arrangement functional groups and
identification of a pharmacophore

3. WHAT IS QSAR ?
is a mathematical relashionship
a biological activity
A QSAR
between
system and its geometric
of a molecular
and chemical
characteristics.
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.

4.  QSAR involves the derivation of mathematical formula
which relates the biological activities of a group of
compounds to their measurable physicochemical
parameters.
 These parameters have major influence on the drug’s
activity. QSAR derived equation take the general form:
 Biological activity = function (parameters)
– Activity is expressed as log(1/c). C is the minimum
concentration required to cause a defined biological
response

5. Physicochemical Parameters
Various parameters used in QSAR studies are:
Hydrophobicity: Partition coefficient,
π-substitution constant
Steric Parameters: Taft’s constant, Hansch
analysis, Verloop steric parameter
Electronic Parameter: Hammet constant,
dipole moment

6. HYDROPHOBICITY
 Hydrophobic character of a drug is crucial to how
easily it cross the cell membrane and may also
important in receptor interactions.
 Hydrophobicity of a drug is measured
experimentally by testing the drugs relative
distribution and is known as partition coefficient

7. Partition coefficient:
Partition coefficient P usually expressed as logP
It is defined as

8. • P is a measure of the relative affinity of a
molecule for the lipid and aqueous phase in
the absence of ionization.
• 1-Octanol is a most frequently used lipid
phase in pharmaceutical research

9. LogP for a molecule can be calculated from a
sum of fragmental or atom based terms plus
various corrections.
LogP = Σ fragments + Σ corrections

10. Relationship between LogP and Log1/C

12. π-substituent constant
The π-substituent constant defined by hansch and co-
workers by the following equation.
Partition coefficient can be calculated by knowing the
contribution that various substituent , is known as
substituent hydrophobicity constant.
πx= log Px-log PH
A positive π value indicates that the π substituent has a
higher hydrophobicity than hydrogen

13. A negative π
Substituent has
indicates that
hydrophobicity
the π
than
value
a lower
hydrogen and the drug favors the aqueous phase.
π identify specific regions of the molecule which
might interact with hydrophobic regions in the binding
sites.

14. ELECTRONIC EFFECT
• The electronic effect of various substituent
will clearly have an effect on drug ionization
and polarity.
• Have an effect on how easily drug can pass
through the cell membrane or how strongly it
can interact with a binding site.
Department of Pharmaceutical
Chemistry

15. The Hammett constant (σ)
sx= log (Kx/K benzoic)
Hammett constant takes into account both
resonance and inductive effects; thus, the value
depends on whether the substituent is para or
meta substituted
• -ortho not measured due to steric effects

21. Molar refractivity

26. 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
Bulky substituent may help to orient a drug
property for maximum binding and increase
activity.

27. Taft’s steric factor (Es)
It is measure by the comparing the rate of
hydrolysis of substituted aliphatic esters against
a standard ester under acidic condition

28. HANSCH EQUATION:
• A QSAR
physicochemical
equation relating
properties to the
various
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.

29. 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 β-halo-β-arylamines

30. CRAIG PLOT
The Craig plot, named after Paul
N. Craig, is a plot of two
substituent parameters used in
rational drug design. Two most
used forms of a Craig plot are
plotting the sigma constants of
hydrophobicity plotting
the Hammett equation versus
the
steric terms of the Taft equation
against hydrophobicity.

31. Advantages:
1. This plot shows that there is no overall relationship
between π & σ
2.Decision can be made about the influence of the
substituent on the biological activity considering positive
& negative at a glance.
3. Substituents containing similar σ & π values can be
identified.
4.It is useful to predict which substituents have to be used
in QSAR studies.

32. PHARMACOPHORE:
 A pharmacophore was first defined by Paul Ehrlich in 1909 as "A
molecular framework that carries (phoros) the essential features
responsible for a drug’s (=pharmacon's) biological activity“.
 In 1977, this definition was updated by Peter Gund to "a set of
structural features in a molecule that is recognized at a receptor site
and is responsible for that molecule's biological activity“.
 The IUPAC definition of a pharmacophore is "an ensemble of steric
and electronic features that is necessary to ensure the optimal
supramolecular interactions with a specific biological target and to
trigger (or block) its biological response".

33. Pharmacophore-based drug design
1. Determine identity of a “lead compound”: Screen
natural and synthetic banks of compounds for
activity
Folk medicine
Natural ligand
Drug already known Computer-
aided drug design
Computerized search of structural databases

34. 2. Data collection: Publications; patents; biological activity;
NMR and X-ray data; physiochemical properties to
determine the effects of structural changes on activity of
drug: structure-activity relationships (SARs)
3. Analysis: Integrate information about drug (and target) to
generate hypothesis about activity. This information will
result in the identification of a pharmacophore.

35. THANK YOU