a ppt about irreversible enzyme inhibitore drugs

1. IRREVERSIBLE ENZYME
INHIBITORS
Sazan J. Ali
Pharmacutical chemistry
department
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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.
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3. Types of irreversible inhibition
 Group-specific covalent modifying
agents
 Affinity labels
 Suicide inhibitors
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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).
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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
KD Kinactivation
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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
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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
KD K2
K4
K
3
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10.  Bind like normal substrate
 Begine, but unable to complete the
reaction
 Get stuck in active site
TS
Inactive
enzyme
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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.
(Mo-S)
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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.
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13Inactive trans peptidase enzyme

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