KENCHA SWATHI-MEDICINAL CHEMISTRY- QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP- VI SEMESTER

1. QSAR
(QUANTITATIVE STRUCTURE
ACTIVITY RELATIONSHIP)
BY
KENCHA SWATHI
ASSISTANT PROFESSOR
DEPT OF PHARMACEUTICAL CHEMISTRY
ADITYA BIPER
BANGALORE

2. QSAR
QSAR is a method developed by “Corwen Hansch”
It is used to quantify the relationship between the
chemical structure of a drug and its biological activity.
QSAR = chemical structure of a Drug x biological
activity.

3. DEFINITION
• QSAR can be defined as a computerized statistical
which gives relevant information regarding the drug to
analyse its biological activity for drug design.

4. • QSAR transforms the chemical structures of a drug or compound ,to set a numerical
parameters or descriptors. Various parameters are
• Physicochemical parameters- solubility, log P ,protein binding, partition coefficient etc..,
• The physicochemical properties are relevant to the biological activity.
• QSAR also applies mathematically derived formulas which correlate the physicochemical
parameters and the biological activity of a drug or compound.
QSAR = f(physicochemical properties) x (biological activity)

5. • QSAR was further assisted by “Louis Hammett”.
• He gave correlation between the electronic properties of organic compound ‘a’ &
‘b’ with its reactivity and equilibrium constant.
Biological activity = f(C)
C = Physicochemical properties and structural descriptors of a
drug
• QSAR is not the final answer to drug discovery but one of the refined tool for
drug development.

6. APPLICATIONS OR OBJECTIVES OF QSAR
• Prediction of Biological activity-with regression analysis or
parameters or their nature and position of substitution .
• QSAR gives positive influence on the compound to be guessed.
• Understanding the mechanism of action of a drug.
• Optimisation of biological activity.
• Lead compound search by CADD

7. • Refinement of synthetic targets.
• Economise the new drug development.
• Reduction of usuage of animals.
• Minimise random synthesis.
• Introduction to drug design

8. LIMITATIONS OF QSAR
• It fails to interpret drug-receptor interaction in
biochemical terms.
• It fails to quantitatively described effects of substituents
on non-covalent intramolecular interactions.

9. QSAR PARAMETERS
Partition coefficient
Hammet’s electronic parameter
Tafts steric parameter
Hansch analysis

10. PARTITION COEFFICIENT
• In a pharmaceutical sciences, partition coefficient is the ration of concentration of a
compound in the two phases of a mixture of two immisible liquids at equilibrium.
• The Partition coefficient is a ratio of concentrations of unionized drug or compound
between the two liquid phases.
• The logarithm of the ratio of concentrations of the unionized solute in the solvents is
called log P..
• One of the solvent is water and the other one is non polar solvent.
• Log P value is also known as a measure of lipophilicity.

11. • For example in octanol-water system is
log P oct/wat = log [solute] unionized
[solute] unionised
log P = log {organic phase}
log {acqueous phase}
log P = log
octanol
water
Unionised compound
octanol
water

12. • Log P is the ideal formula which gives reproducible values on drug absorption.
• If log P value is 0 to 1 shows good biological activity.
• -ve value or 1.2 ,1.5 = no biological activity.
• It is a dimensionless parameter.
• Higher the p value value means ,more the lipophilicity ,more absorption,more
pharmacological activity of the drug.
Log p =lipophilicity+absorption = pharmacological activity of drug
• P value varies with the type of solvent.
• Log P values are reliable index of solubility ,therapeutic activity.

13. HAMMETS ELECTRONIC PARAMETER
• Distribution of electrons in a drug molecule considerably influences the
pharmacokinetic(ADME) & pharmacodynamic activity of the drug.
• The unionized form of polar &non-polar drugs are transported across the lipoidal
membrane against their ionized counter parts.
• When drug reaches to the target site ,the distributed electrons controls the type of the
bond. This bond will form with the target site.
• The bond between target site and the drug molecule shows drug-receptor interaction and
its biological activity.

14. • Hammett substitution constant is a measure of Electron withdrawing group or electron
donating group ability of a drug molecule or its substituent.
• σ value is determined by comparing the dissociation constant of substituted drug with that
of unsubstituted drug.
• When electron withdrawing group is attached to the benzoic acid aromatic ring .It will
increase the acidic strength of –COOH.
• +ve σ value = substituent is Electron withdrawing group.
• -ve σ value = substituent is Electron donating group.

15. • Therefore σ value for hydrogen is zero.
σ = Equilibrium constant for compound
Equilibrium constant for monosubstituted compound
• Hammett constant takes into account both resonance & inductive effect.
• σ value depends on meta or para position.
• Hammett constant gives idea about polarizing capacity,ionization,dipole moment,field
effect,energy of molecular orbit,atomic net energy etc..,

16. TAFTS STERIC PARAMETER
• The interaction of drug with its receptor is markedly influenced by steric factor of a drug.
• The bulk nature of drug,size and shape of the drug influences its binding capacity with an
enzyme or receptors.
• This effect is reflected for the onset of action or duration of action.
• Tafts steric substitution constant ∑ₛ is used for studying the macro molecular steric
effects particularly in reactions wherein substituent is near to its reaction centre.
• Steric parameter uses a computer programme to calculate the steric substituent values like
vanderwals radius, bond length and bond angles etc..,
• Tafts steric parameter influences the biological activity of a drug.

17. DATA ANALYSIS
• The data of biological activity & the values of descriptors or parameters
generated by the softwares should be analysed regressively to get a meaningful
QSAR model (lead model).
• QSAR model is considered as a LEAD model to enter into the preclinical and
clinical trials.
• Cluster analysis and principle component analysis are used to know the better
pharmacological activity.

18. HANSCH ANALYSIS
• Generation of a lead model is a platform used to perform the regression analysis.
• The most frequently used model is ‘HANSCH’ model .
• Hansch model is also called as “LINEAR FREE ENERGY REACTION”model.
log (1/c) = a log p + b
C = molar concentration of the product
a & b = constant values
• Alternative model for analysis is “Free Wilson Approach” model.

19. • The above two methods are used to establish the productiveness of the drug
molecule.
Example: Triazines (6 membered ring containing 3 Nitrogen atoms)
1. Research is going on triazines for anti-cancer activity.
2. Formula log(1/c) = a log p +b
3. If σ value is decreasing and P value is increasing – Lipophilicity and toxicity
increases.
4. If σ value is increasing and P value is decreasing –Lipophilicity and toxicity decreases.
5.Biological activity is normally expressed in log value and is obtained from
invitro experiment using software.
6.Determine the LD₅₀ and ED₅₀ .

20. REFERENCES:
• Wilson and Gisvold’s textbook of pharmaceutical and medicinal chemistry.
• Textbook of medicinal chemistry by Graham Patrick.
• Textbook of Medicinal chemistry by Ashutosh Kar.
• A textbook of medicinal chemistry by Ilango.