Enzymes as Drug Targets - Chapter 7
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Questions and Answers

What is a primary consequence if an enzyme substrate binds too strongly to the active site?

  • The enzyme becomes more efficient at catalysis.
  • The enzyme's active site becomes more selective.
  • The substrate is converted to product very rapidly.
  • The product is not released from the active site. (correct)

    • How does methotrexate inhibit dihydrofolate reductase?

  • By binding to an allosteric site and preventing substrate binding.
  • By acting as a competitive inhibitor preventing folic acid from binding. (correct)
  • By irreversibly binding to the enzyme and changing the active site.
  • By non-competitively binding to the enzyme thus reducing substrate binding.

    • What is the primary action of a competitive enzyme inhibitor?

  • It binds to the enzyme-substrate complex, preventing product formation.
  • It binds to the substrate, making it nonreactive.
  • It binds to the active site, preventing substrate binding. (correct)
  • It binds to an allosteric site, changing the enzyme's conformation.

    • Why is ethanol used as a treatment for ethylene glycol poisoning?

    <p>Ethanol acts as a competitive inhibitor of alcohol dehydrogenase, slowing down the production of toxic metabolites.</p> Signup and view all the answers

    According to the content, what happens if a substrate has a very weak binding affinity for an enzyme?

    <p>The substrate will not remain in the active site long enough for a reaction.</p> Signup and view all the answers

    What does LDLo refer to, as used in the context of toxicology?

    <p>The lowest dose that can produce death.</p> Signup and view all the answers

    In the case of antifreeze poisoning, what is the toxic product that is formed in the body due to an enzymatic reaction?

    <p>Oxalic acid</p> Signup and view all the answers

    How does a competitive inhibitor affect an enzyme's activity?

    <p>It decreases the enzyme’s catalytic rate by blocking substrate binding.</p> Signup and view all the answers

    Type 2 inhibitors primarily target which conformation of the kinase domain?

    <p>The inactive conformation</p> Signup and view all the answers

    What is an uncompetitive inhibitor?

    <p>An inhibitor that binds to the enzyme-substrate complex</p> Signup and view all the answers

    How does a non-competitive inhibitor affect the binding of the substrate to the enzyme?

    <p>It does not affect the binding of the substrate to the enzyme in the ideal case</p> Signup and view all the answers

    What is the role of renin in the regulation of blood pressure?

    <p>It converts angiotensinogen to angiotensin I, which leads to increased blood pressure</p> Signup and view all the answers

    Which of the following best describes the mechanism of action of a non-competitive inhibitor?

    <p>It binds to an allosteric site, causing a conformational change that affects the catalytic mechanism.</p> Signup and view all the answers

    What is a key difference between uncompetitive and non-competitive enzyme inhibitors?

    <p>Uncompetitive inhibitors bind only to the enzyme-substrate complex, while non-competitive inhibitors can bind to both the enzyme and the enzyme-substrate complex</p> Signup and view all the answers

    Which of the following is a key characteristic of an uncompetitive inhibitor?

    <p>Its effectiveness is enhanced at higher substrate concentrations.</p> Signup and view all the answers

    What is a primary function of the SH3 domain in the context of the BCR-ABL fusion gene?

    <p>It serves as a negative regulatory domain.</p> Signup and view all the answers

    Which antiviral drug is specifically used for herpes treatment?

    <p>Acyclovir</p> Signup and view all the answers

    What is the main role of kinase enzymes in cellular processes?

    <p>Catalyzing the phosphorylation of proteins</p> Signup and view all the answers

    Which of the following is an enzyme modulator that acts as a vasodilator?

    <p>Riociguat</p> Signup and view all the answers

    Which enzyme inhibitor is mentioned in research related to anticancer agents?

    <p>Aromatases</p> Signup and view all the answers

    What potential benefit does inhibiting caspases have?

    <p>Treatment of stroke victims</p> Signup and view all the answers

    What is the primary cause of BCR-ABL formation?

    <p>A chromosomal translocation</p> Signup and view all the answers

    What is the main characteristic of BCR-ABL that leads to cancer progression?

    <p>Constitutive kinase activity</p> Signup and view all the answers

    How do allosteric inhibitors differ from ATP-competitive inhibitors?

    <p>They bind to a site remote from the catalytic site</p> Signup and view all the answers

    What is a key advantage of allosteric inhibitors compared to type 1 inhibitors?

    <p>They are highly selective for BCR-ABL, minimizing damage to normal cells.</p> Signup and view all the answers

    How can allosteric inhibitors be used in combination with ATP-competitive inhibitors?

    <p>They can be combined to achieve a synergistic effect for greater efficacy.</p> Signup and view all the answers

    Which drug is an inhibitor of the cyclooxygenase enzyme and is used for anti-inflammatory purposes?

    <p>Aspirin</p> Signup and view all the answers

    Type 1 kinase inhibitors bind to which conformation of the kinase?

    <p>The active conformation.</p> Signup and view all the answers

    Which of the following drugs targets the angiotensin-converting enzyme for antihypertension treatment?

    <p>Captopril</p> Signup and view all the answers

    What is a primary disadvantage of Type 1 inhibitors?

    <p>They may cause off-target effects due to binding to other kinases.</p> Signup and view all the answers

    In what case would type 2 inhibitors be considered when compared to type 1 inhibitors?

    <p>When resistance or intolerance to type 1 inhibitors develops.</p> Signup and view all the answers

    Which drug is associated with the treatment of Parkinson's disease and inhibits monoamine oxidase-B?

    <p>Selegiline</p> Signup and view all the answers

    Which drug is not used as an anticancer medication but rather as a treatment for erectile dysfunction?

    <p>Sildenafil</p> Signup and view all the answers

    Which of these drugs is primarily used to lower cholesterol levels?

    <p>Simvastatin</p> Signup and view all the answers

    What is the primary role of renin in the body?

    <p>To participate in the renin–angiotensin–aldosterone system</p> Signup and view all the answers

    What characterizes the transition state of substrates in enzyme-catalyzed reactions?

    <p>It has a tetrahedral geometry</p> Signup and view all the answers

    How do renin transition-state analogues function as drugs?

    <p>By binding more strongly to the transition state</p> Signup and view all the answers

    What is a characteristic feature of suicide inhibitors?

    <p>They undergo transformation to form a covalent bond</p> Signup and view all the answers

    Which of the following statements about clavulanic acid is true?

    <p>It acts as a suicide substrate against β-lactamases</p> Signup and view all the answers

    What is a significant limitation when isolating the high-energy state during renin-catalyzed hydrolysis?

    <p>The high-energy state cannot be isolated</p> Signup and view all the answers

    What determines the effectiveness of a transition-state analogue drug?

    <p>Its resemblance to the reaction intermediate</p> Signup and view all the answers

    Which of the following roles does renin play in the renin-angiotensin-aldosterone system?

    <p>Catalyzes the hydrolysis of specific peptides</p> Signup and view all the answers

    Study Notes

    Enzymes as Drug Targets

    • This chapter (7) covers enzymes as drug targets in medicinal chemistry (CH456).
    • Various types of enzyme inhibitors are discussed, including those acting at the active site, allosteric binding sites, uncompetitive and non-competitive inhibitors, transition-state analogues (like Renin inhibitors), and suicide substrates.
    • Specific examples are given such as competitive inhibitors, the use of methotrexate to inhibit dihydrofolate reductase, and the use of inhibitors in antifreeze poisoning.

    Reversible Inhibitors

    • Substrate binding at the enzyme's active site must be strong enough to enable the reaction, but not too strong to cause product release issues.
    • Substrates that bind too weakly will not remain long enough to enable a productive reaction.
    • Too strong of binding can prevent the product from being released, causing issues.

    Competitive Inhibitors

    • Competitive inhibitors have structures similar to natural substrates or products.
    • Competitive inhibitors bind more strongly to the active site.
    • This competition between the drug and natural substrate reduces the rate of product formation and has a greater effect the longer the drug remains in the site.
    • Dihydrofolate reductase, which is prevented from binding to its substrate folic acid.

    Irreversible Inhibitors

    • Irreversible inhibitors form covalent bonds with key amino acids within active sites.
    • They tend to be more effective due to their stronger binding.
    • Some common functional groups in these inhibitors include alkyl halides, epoxides, and α,β-unsaturated ketones, and some highly toxic nerve agents contain these properties.

    Allosteric Binding Sites

    • Enzymes can be regulated by naturally occurring allosteric inhibitors.
    • An inhibitor binding to an allosteric site can change the conformation of the active site.
    • Certain drugs can mimic this natural activity, causing reversible or irreversible inhibition depending on the drug.
    • Examples of such drugs include 6-mercaptopurine which inhibits the first enzyme in synthesis of certain compounds, and is used to treat leukemias.

    BCR-ABL Inhibitors

    • BCR-ABL is a fusion protein resulting from a chromosomal translocation between chromosomes 9 and 22.
    • This protein shows constitutive activity, which contributes to unregulated cell proliferation.
    • Allosteric inhibitors target BCR-ABL by binding to a regulatory site remote from the catalytic site.
    • These inhibitors bind to the inactive conformation or the active conformation and can reduce side effects.
    • Types of inhibitors have different binding sites, such as type 1 that target active sites for enzyme inhibitors, and type 2 inhibitors that target inactive sites for enzyme inhibition.

    Renin and Hypertension

    • Renin is an enzyme that converts angiotensinogen into angiotensin I.
    • Angiotensin I is further converted to angiotensin II, a potent vasoconstrictor that increases blood pressure.
    • Angiotensin II, a peptide hormone, is also converted and inhibits the renin enzyme.

    Renin Transition-State Analogues

    • Renin transition-state analogs mimic the transition state.
    • Designing these drugs is based on the reaction intermediate, aiming for stronger binding than that of the substrate or product.
    • The transition state is more tetrahedral in nature than the substrate.
    • Clavulanic acid and other transition-state-like drugs are often used.

    Suicide Inhibitors

    • These are designed to undergo enzymatic transformation leading to covalent bond formation.
    • Clavulanic acid is an example that inhibits bacterial enzymes.
    • These molecules undergo enzymatic transformation, and they result in highly reactive species that irreversibly bind the enzyme active site.

    Isozyme Selectivity

    • Tissue-selective drugs target isozymes of the same enzyme.
    • The specificity allows them to target tissues more precisely.
    • Cyclooxygenase (COX) isozymes, particularly COX-2, are examples of tissue-specific isozymes.
    • Drugs like valdecoxib, rofecoxib, and celecoxib are specifically designed to target COX-2, reducing the side effects of inhibiting other isozymes.

    Enzyme Inhibitors Used Against Microorganisms

    • Target enzymes crucial for microorganisms but absent or different in human enzymes.
    • Natural product screening is common.
    • Antibiotic drugs act as enzyme inhibitors to microorganisms, such as penicillin inhibiting bacterial enzymes.

    Enzyme Inhibitors Used Against Viruses

    • Enzyme inhibitors work in combating viral infections.
    • Specific drugs such as aciclovir fight herpesviruses.
    • Zidovudine (AZT) and saquinavir target HIV, impacting the virus lifecycle.

    Enzyme Inhibitors Used Against Body's Own Enzymes

    • Research on enzyme inhibitors for the body's own enzymes continues.
    • Several enzymes, such as isozymes of COX, matrix metalloproteinases, aromatase, and caspases, are significant targets in research.
    • Targeting these enzymes can treat diseases such as rheumatoid arthritis, cancers, and stroke.

    Enzyme Modulators

    • Enzyme modulators bind to allosteric sites and modify enzyme activity.
    • Modulators increase the enzyme's sensitivity to low substrate levels or alter enzyme conformation between active and inactive states.
    • Riociguat modulates soluble guanylate cyclase, a vasodilator.

    Summary of Key Points

    • Enzyme inhibition can be reversible or irreversible based on the drug's mechanism of action.
    • Competitive inhibitors occupy the active site preventing substrate binding.
    • Allosteric inhibitors alter the enzyme's shape through binding to a different site, impacting its function.
    • Transition-state analogues mimic the high-affinity transition state.
    • Suicide substrates are molecules that become highly reactive and essentially become irreversible inhibitors.
    • Isozyme selectivity is critical to avoid side effects in multiple tissues.
    • Enzyme inhibitors have many medicinal applications.

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    Enzymes As Drug Targets PDF

    Description

    Dive into Chapter 7 of medicinal chemistry, focusing on enzymes as drug targets. Explore various types of enzyme inhibitors, including competitive, allosteric, and transition-state analogues, along with specific examples like methotrexate and its role in inhibiting dihydrofolate reductase. Understand the delicate balance of substrate binding for effective enzymatic reactions.

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