Department of Biochemistry and Molecular Biology, New Jersey Medical School

1
Enzyme Inhibition-Drug Design

• Aspirin
• Penicillin
• Sulfonamides
• Steroid creams
• Anti HIV drugs

2
ENZYME INHIBITORS AS DRUGS

• Inhibitors

Competitive Non-competitive Irreversible
Compet. 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 at the site covalent
bond with a group at this site
3
COMPETITIVE INHIBITORS

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

4
COMPETITIVE INHIBITORS

• Km(app) is increased Vmax remains unchanged

5
COMPETITIVE INHIBITORS AS DRUGS
Thioadenine
Adenine
6
METHOTREXATE

• An anticancer drug that is a competitive
  inhibitor of dihydrofolate reductase

7
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

8
NONCOMPETITIVE INHIBITION

• E S ES E P
• I I
• Ki Ki
• EI ESI
• Vmax S
• V 1(I/Ki)
• Km S

9
NONCOMETITIVE INHIBITION

• Km is unchanged but Vmax is decreased

10
Non-competitive inhibitors as drugs

• Fluoride Non-competitive inhibitor of enolase
• Non-nucleoside compounds as inhibitors of HIV RT

11
IRREVERSIBLE INHIBITORS
E S ES E P I EI
E----I (Inactive covalent complex)
Irrev. Inh
Enzyme
12
EXAMPLES OF IRREVERSIBLE INHIBITORS AS DRUGS
13
Amoxicillin and Clavulinic Acid
14
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

15
ENZYME INHIBITORS IN CLINICAL USE

• A clinical application in Periodontitis