This document discusses various applications of quantitative structure-activity relationships (QSAR) in drug research and development. It describes how QSAR can provide information on receptor sites from enzyme inhibition studies, help understand the importance of physicochemical properties like log P values, and enable the use of bioisosterism to modify compounds. QSAR has correctly predicted drug activity and toxicity and is useful in drug design before compounds are synthesized.

1. APPLICATIONS OF QSAR
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2. 2Department of pharmaceutical chemistry

3. 1. Information from the intercept values
2. Importance of log P0 concept
3. Bioisosterism
4. Enzyme Inhibition
5. Information on receptor site
6. Importance in Drug Research
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4. 1. Information from the intercept values
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5. • Intercept represents the activity of the unsubstituted
compound
• The activity increases or decreases depending on the
substitution which is reflected in the slope or regression
coefficient.
• Intercept is very high and slope is low- basic nucleus or the
parent compound has high activity.
• Intercept is a measure of intrinsic activity.
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6. • Similar slope or correlation coefficients.
•Intercept are different.
•Carbamates are more active.
Examples
1. Alcohol and Carbamates inhibit bacterial
luminescence
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7. Example 2
Esters and alkyl carbonates -their narcotic action on
tadpoles.
Carbamates are more active than
the esters.
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8. 2. Importance of log P0 concept
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9. EXAMPLES
Analgesic activity of
Hydroxycodenone esters :
Anticonvulsant activity
(barbiturates, benzodiazepines
etc ) :
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10. • General anesthetic activity of ethers.
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11. 11Department of pharmaceutical chemistry

12. The logP value of many CNS drug was around 2.0.
For example:
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13. 3. Bioisosterism
• Replacement of one fuctional group with other having similar
properties both qualitatively and quantitatively.
• Discovery of cyanoguanidine as the bioisostere of thiourea,
• Development of H2 antagonists.
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14. EXAMPLE
A guanidine isostere, where C=S is replaced with C=NH, resulted
in increased basicity and reduced activity. To decrease the basicity,
an electron withdrawing group like NO2 , -CN were introduced
into the guanido group.
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15. • Cyanoguanidine group – NH(C=NCN)-NH- =
ideal isoster for thiourea –NH(C=S) -NHR with
reduced basicity.
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16. • Thiourea is replaced with –– NH(C=CHNO2) –NHR group.
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17. 4. Enzyme Inhibition
• Dihydrofolate reductase (DHFR) most extensively
investigated enzyme.
• DHFR inhibitors are therapeutically important as highly
selective in
• Antibacterial
• Antimalarial
• Antitumor agents
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19. • Replacement of one methoxy group of trimethoprim by an
acidic side chain - carboxylate group- increase in inhibitory
activities but selectivity and membrane permeability
significantly decreased.
• Replacement to sulfonyl group- Mycobacterium lufu DHFR
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20. • Potent in vitro inhibitor of Escherichia coli DHFR.
• Both bacteria largely differ in the permeability of their cell
walls.
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21. 5. Information on receptor site
• Inhibition of dihydro folate reductase(DHFR) by benzyl
pyrimidines (Trimethoprim type).
• Inhibition of DHFR from bovine liver and from E.coli.
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22. • Mammalian enzyme –hydrophobicity
• Bacterial inhibition depends on the bulk of the substituent.
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23. • QSAR on Quinazolines- hydrophobic parameter for the
substituent at 5 positions - a large positive coefficient.
• Hydrophobic pocket - both mammalian and bacterial DHFR.
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24. • Triazines - hydrophobic pocket is larger in bacterial enzyme
than the mammalian enzyme.
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25. 6. Importance in Drug Research
• QSAR has correctly predicted the activity of large number of
compounds before their synthesis.
• Colchicine -anti-cancer drug - toxicity
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26. • I is the indicator variable for the presence of the group -COCH3
at 10 position.
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27. • Toxicity studies on the same data resulted in equation:
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28. reference
• Medicinal chemistry by Burger, Wiley Publications Co.
• An introduction to medicinal chemistry- Graham.L.Patrick ,page no: 383
• The organic chemistry of the drug design and drug action – Richard. B. Silverman.
• QSAR: Hansch Analysis and Related Approaches- Hugo Kubinyi . vol :1, page no;
115
• QSAR - Application in Drug Design- International Journal of Pharmaceutical
Research & Allied Sciences, vol: 2. Page no: 6
• Application of QSAR in Drug Design and Drug Discovery- World Journal of
Clinical Pharmacology, Microbiology and Toxicology, Vol. 1, page no: 28.
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