Lecture 7-Kumar Enzyme Inhibition-Drug Discovery Aspirin (anti-inflammatory) Penicillin (effective against gram positive bacteria) Sulfonamides (anti-diarrhea)

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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 1

2 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 3

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

Kinetics of competitive inhibitor binding Increase [S] to overcome inhibition V max attainable, Apparent K m is increased K i = dissociation constant for inhibitor 5

V max unaltered, K m increased Double reciprocal plot in the presence of a competitive inhibitor 6

Methotrexate in cancer chemotherapy 7

COMPETITIVE INHIBITORS AS DRUGS Adenine Thioadenine 8

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 9

ENZYME INHIBITORS IN CLINICAL USE A clinical application in Periodontitis 10

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

Kinetics of non-competitive inhibition Increasing [S] cannot overcome inhibition Less E available, V max is lower, K m remains the same for available E 12

Noncompetitive inhibition K m unaltered, V max decreased 13

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

Kinetics of irreversible inhibition 15

EXAMPLES OF IRREVERSIBLE INHIBITORS AS DRUGS 16

Amoxicillin and Clavulinic Acid 17

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 18

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 19