APPLICATIONS OF QSAR

QSAR

1. APPLICATIONS OF QSAR 1 Department of pharmaceutical chemistry

2. 2 Department of pharmaceutical chemistry

3. Information from the intercept values Importance of log P concept Bioisosterism Enzyme Inhibition Information on receptor site Importance in Drug Research 3 Department of pharmaceutical chemistry

4. 1. Information from the intercept values 4 Department of pharmaceutical chemistry

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. 5 Department of pharmaceutical chemistry

6. Similar slope or correlation coefficients. Intercept are different. Carbamates are more active. Examples 1. Alcohol and Carbamates inhibit bacterial luminescence 6 Department of pharmaceutical chemistry

7. Example 2 Esters and alkyl carbonates -their narcotic action on tadpoles. Carbamates are more active than the esters. 7 Department of pharmaceutical chemistry

8. 2. Importance of log P concept 8 Department of pharmaceutical chemistry

9. EXAMPLES Analgesic activity of Hydroxycodenone esters : Anticonvulsant activity (barbiturates, benzodiazepines etc ) : 9 Department of pharmaceutical chemistry

10. General anesthetic activity of ethers. 10 Department of pharmaceutical chemistry

11. 11 Department of pharmaceutical chemistry

12. The logP value of many CNS drug was around 2.0. For example: 12 Department of pharmaceutical chemistry

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 H 2 antagonists. 13 Department of pharmaceutical chemistry

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 NO 2 , -CN were introduced into the guanido group. 14 Department of pharmaceutical chemistry

15. Cyanoguanidine group – NH(C=NCN)-NH- = ideal isoster for thiourea –NH(C=S) -NHR with reduced basicity . 15 Department of pharmaceutical chemistry

16. Thiourea is replaced with –– NH(C=CHNO 2 ) –NHR group. 16 Department of pharmaceutical chemistry

17. 4. Enzyme Inhibition Dihydrofolate reductase (DHFR) most extensively investigated enzyme. DHFR inhibitors are therapeutically important as highly selective in Antibacterial Antimalarial Antitumor agents 17 Department of pharmaceutical chemistry

18. 18 Department of pharmaceutical chemistry

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 19 Department of pharmaceutical chemistry

20. Potent in vitro inhibitor of Escherichia coli DHFR. Both bacteria largely differ in the permeability of their cell walls. 20 Department of pharmaceutical chemistry

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 . 21 Department of pharmaceutical chemistry

22. Mammalian enzyme – hydrophobicity Bacterial inhibition depends on the bulk of the substituent. 22 Department of pharmaceutical chemistry

23. QSAR on Quinazolines - hydrophobic parameter for the substituent at 5 positions - a large positive coefficient. Hydrophobic pocket - both mammalian and bacterial DHFR. 23 Department of pharmaceutical chemistry

24. Triazines - hydrophobic pocket is larger in bacterial enzyme than the mammalian enzyme. 24 Department of pharmaceutical chemistry

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 25 Department of pharmaceutical chemistry

26. I is the indicator variable for the presence of the group -COCH 3 at 10 position. 26 Department of pharmaceutical chemistry

27. Toxicity studies on the same data resulted in equation: 27 Department of pharmaceutical chemistry

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. 28 Department of pharmaceutical chemistry