Drug action: Targets

Enzyme-Substrate Kinetics Fundamentals

• A chemotherapeutic drug's effects are influenced by enzyme-substrate and receptor-ligand interactions.
• The course of drug administration flows from the total oral dosage to the drug reaching the site of action.

Drug Targets and Action Concepts

• Drug targets, including receptors and enzymes, are key to comprehending drug action.
• Drug action is either specific, targeting the disease agent directly, or non-specific, alleviating symptoms.
• Drugs effects occur directly at the point of action or remotely to produce similar effects on the body.

Drug Targets

• Approved drugs' molecular targets have been debated for a decade.
• 3578 all targets were identified in 2022, in the therapeutic target database.
• The therapeutic target database also reports data that there are 38.760 all drugs, as of 2022.
• Target classes include receptors (193), enzymes (124), and transporters (67).
• Receptors are the most common therapeutic target class in drug discovery 45%, followed by enzymes 28%.

Enzyme Action Catalysis

• Catalysts reduce it, allowing reactions to proceed faster.
• Enzymes catalyze reactions by initially binding to a substance.
• Binding generates an enzyme-substrate complex, which forms an enzyme-product complex and releases the goods.
• Enzyme-catalyzed reaction rate changes with substrate concentration.

Enzyme Action Modification

• Enzymes bind to a substrate (S), forming a complex (ES) that leads to a product (E+P), influenced by rate constants.
• Michaelis-Menten constant, or KM, affects reaction velocity relative to substrate concentration.
• Lineweaver-Burk plots are used to analyze enzyme kinetics and inhibition
• Enzymatic and receptor processes share similarities, like binding molecules and regulation.

Enzyme Inhibition

• Enzyme inhibition includes classical reversible, mechanism-based reversible, and irreversible types.
• Classical reversible enzyme inhibition is divided into competitive and non-competitive inhibition.
• Transition state analogs that mimic reactive chemicals inhibit enzymes acting as mechanism-based reversible enzyme inhibitors
• Reaction coordinate analogs react with the active site to form a covalent complex that slows production, but is reversible

Reversible Enzyme Inhibition Types

• Competitive inhibitors bind to the active site, can be overcome by high substrate concentrations, and allow Vmax attainment
• Non-competitive inhibitors binds elsewhere on the enzyme, cannot be overcome by substrate, and doesn't allow Vmax attainment.

One Carbon Metabolism

• 5,10-methylenetetrahydrofolate is required for nucleic acid production, and 5-methyltetrahydrofolate is used to make methionine from homocysteine
• The first purine created in the de-novo biosynthesis route is inosine monophosphate.
• Inosine monophosphate is created using atoms got from the folate pathway, plus some amino acid building blocks.

Competitive Inhibitors

• Sulfanilamide inhibits dihydropteroate synthase by mimicking PABA, impacting folate synthesis for bacterial growth.

Non-Competitive Inhibitors

• 6-Mercaptopurine inhibits the conversion of inosine monophosphate to adenine/guanine as a purine antagonist.
• 6-MP converts to TIMP which inhibits de novo purine-ring biosynthesis and then converts to TGMP, inhibiting DNA/RNA

Irreversible Enzyme Inhibition

• Mechanism-based irreversible enzyme inhibition and Irreversible Reaction Coordinate Inhibitors
• With Penicillin, transpeptidase is needed for bacterial wall synthesis.
• Irreversible inhibitors use affinity labels (ex. chloromethyl ketones) for active sites, but could be harmful as drugs

Suicide Substrates

• Suicide substrates, (Kcat) Inhibitors such as clavulanic acid, inhibits beta-lactamase (which is not a cell wall biosynthesis inhibitor)
• Fluorine prevents enzyme release in 5-FU, blocking thymidylate production needed for DNA synthesis.