Lecture 7-Enzyme Inhibition-Drug Discovery Meisenberg

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Lecture 7-Kumar
Enzyme 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
+
I
ES
E + P
EI
Ki= [E][I]/[EI]
V= Vmax S
Km[1+(I/Ki)] +S
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Kinetics of competitive inhibitor binding
Ki =
dissociation
constant for
inhibitor
Increase [S] to
overcome
inhibition
Vmax attainable,
Apparent Km is increased
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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
+
I
EI + S
ES
+
I
E + P
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 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, noncompetitive 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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