Irreversible enzyme inhibitores

a ppt about irreversible enzyme inhibitore drugs

1. IRREVERSIBLE ENZYME INHIBITORS Sazan J. Ali Pharmacutical chemistry department 1

2. Irreversible enzyme inhibitors : Are binding covalently or non covalently to the enzyme and permanently inhibit it. there is no reversal of inhibition on decreasing the inhibitor concentration . 2

3. Types of irreversible inhibition Group-specific covalent modifying agents Affinity labels Suicide inhibitors 3

4. 1.Group specific covalent modifying agents: react with specific type of enzyme functional group (e.g., Ser -OH, or Cys -SH, or His imidazole) on any enzyme/protein React with amino acid side chains. Lead to inhibition by interfering with the catalysis (e.g. by reacting with side-chains important for the catalysis ) E.g. diisopropyl fluorophosphate ( DFP) , Nerve gas. Inhibits acetylcholine esterase (and many other proteases with Ser at the active site ). 4

5. 5

6. 2.Affinity labeling agents (reactive based analog ) Active-site directed irreversible inhibitors. Recognized by the enzyme (reversible, specific binding) followed by covalent bond formation. structurally similar to substrate, transition state or product allowing for specific interaction between the compound and target enzyme . E+I E  I E-I K D K inactivation 6

7. Affinity labels(reactive based analog) Structural similarity to substrate guides reagent to the active site of enzyme. It is a common and powerful tool to isolate and characterize the enzymes More specific than group specific reagents. Tosyl phenylalanin chloromethylketon (TPCK) irreversibly in activate chymotrypsin 7

8. 8

9. 3. Mechanism-based enzyme inactivators (Suicide Inhibitors) Active-site directed reagent (unreactive) binds to the enzyme active site  transformed to a reactive form. Once activated, a covalent bond between the inhibitor and the enzyme forms This approach minimizes side reactions (non specific covalent bond formation) which may occur with an affinity reagent E+I E..I E..I E-I E+P 1) inhibitor binds to active site 2) converted to reactive compound via enzyme's catalytic capabilities 3) covalently reacts with the enzyme Inactivation (covalent bond formation, k4) must occur prior to dissociation (k3) otherwise the now reactive inhibitor is released into the environment K D K 2 K 4 K 3 9

10. Bind like normal substrate Begine , but unable to complete the reaction Get stuck in active site TS Inactive enzyme 10

11. Allopurinol - the anti-gout drug - is a suicidal irreversible mechanism-based inhibitor of the enzyme xanthine oxidase that works as oxidase or dehydrogenase. The enzyme commits suicide by initial activating allopurinol into a transition state analog - oxypurinol - that bind very tightly to molybdenum-sulfide (Mo-S) complex at the active site . The molybdenum-sulfide (Mo-S) complex binds the substrates and transfers the electrons required for the oxidation reactions. (M o -S) 11

12. Suicide inhibitors - penicillin Interfere with the synthesis of the bacterial cell wall. Makes bacteria much less resistant to stress . Penicillin blocks the formation of the link between the tetra peptide and the pentaGly bridge. 12

13. jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 13 Inactive trans peptidase enzyme

14. Thanks for your attention 14