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Lecture 7-KumarEnzyme Inhibition-Drug Discovery
• Aspirin (anti-inflammatory)• Penicillin (effective against gram positive
bacteria)• Sulfonamides (anti-diarrhea)• Anti HIV drugs
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ENZYME INHIBITORS AS DRUGS
• 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 inhibition
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COMPETITIVE INHIBITORS
E + S ES E + P+I
EIKi= [E][I]/[EI]
V= Vmax S Km[1+(I/Ki)] +S
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Kinetics of competitive inhibitor bindingIncrease [S] toovercomeinhibition
Vmax attainable,Apparent Km is increased
Ki =dissociationconstant forinhibitor
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Vmax unaltered, Km increased Double reciprocal plot in the
presence of a competitive inhibitor
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Methotrexate in cancer chemotherapy
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COMPETITIVE INHIBITORS AS DRUGS
Adenine Thioadenine
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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
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ENZYME INHIBITORS IN CLINICAL USE • A clinical application in Periodontitis
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NONCOMPETITIVE INHIBITION
E + S ES E + P+ +I I
EI + S ESI
Vmax SV= [1+(I/Ki)] Km + S
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Kinetics of non-competitive inhibitionIncreasing [S] cannotovercome inhibition
Less E available,Vmax is lower,Km remains the samefor available E
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Noncompetitive inhibition
Km unaltered, Vmax decreased
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Non-competitive inhibitors as drugs
• Fluoride: Non-competitive inhibitor of enolase
• Non-nucleoside compounds as inhibitors of HIV RT
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Kinetics of irreversible inhibition
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EXAMPLES OF IRREVERSIBLE INHIBITORS AS DRUGS
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Amoxicillin and Clavulinic Acid
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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
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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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