Enzyme Inhibition and Inactivation

1. Enzyme Inhibition and Inactivation Objectives: A significant number of drugs act by inhibiting specific enzymes.  Upon completion of the lecture students will know concepts associated with drugs that target enzymes, including irreversible enzyme inhibitors, with particular emphasis on the antihypertensive drugs that inhibit the enzyme, angiotensin converting enzyme.  In addition, concepts associated with drug resistance and drug synergism in enzyme based inhibitors will be presented

2. Antimetabolites i) Chemotherapy ii) Treatment of gout iii) Unique metabolic pathways in non mammalian species

3. Classes of Reversible Enzyme Inhibition Competitive inhibitors Non-competitive inhibitors Slow-binding or tight-binding inhibitors Transition state analogs Multisubstrate Analogs

4. Irreversible Enzyme Inhibitors Drive equilibrium fully to the right:

5. Aspirin Natural product Salicin converted to salicyclic acid Bayer: developed acetylsalicylate Irreversible inhibitor of prostaglandin biosynthesis via inactivation of prostaglandin synthase (cyclooxygenase) Celebrex

6. Specific Irreversible Enzyme Inhibitors Affinity Labeling Agents

7. MPTP:enzyme activatated irreversible inhibitor

8. Drug Resistance  1) Altered uptake 2) Overproduction of target enzyme 3) Altered target enzyme 4) Production of a Drug-Destroying Enzyme 5) Deletion of a Prodrug-Activating Enzyme 6) Overproduction of Substrate for Target Enzyme 7) New metabolic pathway

9. Drug Synergism 1) Inhibition of a Drug-Destroying Enzyme 2) Sequential Blocking 3) Inhibition of enzymes in different metabolic pathways 4) Multiple drugs for the same target

10. Antihypertensive Drugs in the Renin-Angiotensin System Captopril, Enalapril, Lisinopril (others) Angiotensin II i) vasoconstrictor ii) releases aldosterone: controls electrolyte balance Converted from Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-\-His-Leu Bradykinin: vasodilator Arg-Pro-Pro-Gly-Phe-Ser-Pro-\-Phe-Arg Both reactions catalyzed by the angiotensin converting enzyme (ACE)

11. Design of ACE inhibitors Natural product inhibitors identified BPP5a: Ki: 0.09 uM Glu-Lys-Trp-Ala-Pro Teprotide: Ki: 0.84 uM Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro i) optimize structural features based on essential amino acids ii) minimize peptidic character iii) introduce transition state analog

12. Model of the interaction of the angiotensin inhibitors with the active site of angiotensin-converting enzyme

13. Catalytic mechanism of ACE and a comparison of the structure of the drug Enalaprilat with the two transition states

14. Enalapril and Fosinopril: prodrugs

15. Recent ACE inhibitors