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Lecture 7-Enzyme Inhibition-Drug Discovery

Lecture 7-Enzyme Inhibition-Drug Discovery. Aspirin (anti-inflammatory) Penicillin (effective agaist gram posiytive) Sulfonamides (anti-diarrhea) Anti HIV drugs. Competitive Inhibitors compete with the substrate for the active site

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Lecture 7-Enzyme Inhibition-Drug Discovery

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  1. Lecture 7-Enzyme Inhibition-Drug Discovery • Aspirin (anti-inflammatory) • Penicillin (effective agaist gram posiytive) • Sulfonamides (anti-diarrhea) • Anti HIV drugs

  2. Competitive Inhibitors compete with the substrate for the active site • Non-Competitive inhibitors bind near but not at the active site • Irreversible inhibitors bind at the active site of the enzyme and form a covalent bond with a group at this site ENZYME INHIBITORS AS DRUGS

  3. Enzyme inhibition

  4. COMPETITIVE INHIBITORS E + S ES E + P + I EI Ki= [E][I]/[EI] V= Vmax S Km[1+(I/Ki)] +S

  5. Kinetics of competitive inhibitor binding Increase [S] to overcome inhibition Vmax attainable, Apparent Km is increased Ki = dissociation constant for inhibitor

  6. Vmax unaltered,Km increased Double reciprocal plot in the presence of a competitive inhibitor

  7. Methotrexate in cancer chemotherapy

  8. COMPETITIVE INHIBITORS AS DRUGS Thioadenine Adenine

  9. More competitive inhibitors as drugs • Doxycycline • competitive inhibitor of collagenase- control of periodontal disease • AZT-competitive inhibitor of HIV RT • Mozenavir and Tipranavir competitive inhibitors of HIV protease • Allopurinol (used in gout)—Oxypurinol—inhibits xanthine oxidase

  10. ENZYME INHIBITORS IN CLINICAL USE • A clinical application in Periodontitis

  11. NONCOMPETITIVE INHIBITION E + S ES E + P + + I I EI + S ESI Vmax S V= [1+(I/Ki)] Km + S

  12. Kinetics of non-competitive inhibition Increasing [S] cannot overcome inhibition Less E available, Vmax is lower, Km remains the same for available E

  13. Noncompetitive inhibition Km unaltered,Vmax decreased

  14. Non-competitive inhibitors as drugs • Fluoride: Non-competitive inhibitor of enolase • Non-nucleoside compounds as inhibitors of HIV RT

  15. Kinetics of irreversible inhibition

  16. EXAMPLES OF IRREVERSIBLE INHIBITORS AS DRUGS

  17. Amoxicillin and Clavulinic Acid

  18. Irreversible Inhibitors • Emphysema: Alpha-1-Antitrypsin deficiency—This protein inhibitor irreversibly inactivates elastase • Nerve Gas: Sarin—irreversibly inhibits acetylcholinesterase and conversion of acetylcholine to choline and acetic acid • Anticancer Drug: 5-Fluorouracil—irreversibly inhibits thymidylate synthetase

  19. Lecture 7-Learning objectives • Recognize the differences between competitive, non-competitive and irreversible inhibitors • Know how each of the inhibitors affects Km and Vmax • Know the importance of inhibition constant in drug design and discovery • Be knowledgeable about some of the drugs currently on the market

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