Lecture 7-Kumar Enzyme Inhibition-Drug Discovery

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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

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Enzyme inhibition
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COMPETITIVE INHIBITORS

• E S ES E P
• I
  
• EI
• Ki EI/EI
• V Vmax S
• Km1(I/Ki) S

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Kinetics of competitive inhibitor binding
Increase S to overcome inhibition Vmax
attainable, Apparent Km is increased
Ki dissociation constant for inhibitor
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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
Thioadenine
Adenine
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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)Oxypurinolinhibits
  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 S
• V 1(I/Ki)
• Km S

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Kinetics of non-competitive inhibition
Increasing S cannot overcome inhibition Less E
available, Vmax is lower, Km remains the same for
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 deficiencyThis
  protein inhibitor irreversibly inactivates
  elastase
• Nerve Gas Sarinirreversibly inhibits
  acetylcholinesterase and conversion of
  acetylcholine to choline and acetic acid
• Anticancer Drug 5-Fluorouracilirreversibly
  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