Enzymes as Drug Targets - Chapter 7

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.

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.