Podcast
Questions and Answers
Can curves tell us whether naloxone is a reversible or irreversible binder?
Can curves tell us whether naloxone is a reversible or irreversible binder?
Yes
How can the mode of action of a medicine be determined?
How can the mode of action of a medicine be determined?
By studying its effects and interactions with biological targets.
Why is it important to determine the mode of action of a drug?
Why is it important to determine the mode of action of a drug?
To understand how the drug works and its potential effects.
What was Prontosil shown to be in 1935?
What was Prontosil shown to be in 1935?
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What does aspirin acetylate?
What does aspirin acetylate?
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Aspirin inhibits prostaglandin production.
Aspirin inhibits prostaglandin production.
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What is the initial focus of Tristan de Rond's Chem390 section?
What is the initial focus of Tristan de Rond's Chem390 section?
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What is the definition of abscissa?
What is the definition of abscissa?
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Which of the following statements about enzyme kinetics is true?
Which of the following statements about enzyme kinetics is true?
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What is the primary mode of action study for sulfonamides?
What is the primary mode of action study for sulfonamides?
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Study Notes
Naloxone and Mode of Action of a Drug
- Determining the mode of action of a drug is crucial, despite knowing the target, to understand the drug's effect on the body
- Mode of action studies can be either molecular target-based or phenotype-based
Sulfonamides: The First Mode of Action Study
- Sulfonamides were the first widely-used antibacterials
- Prontosil was shown to be a prodrug in 1935
- The mode of action of sulfanilamide was discovered by adding extra nutrients, such as yeast extract, to bacteria, which made them withstand sulfanilamide better
- The "Factor" in yeast extract that protects against sulfanilamide was found to be para-aminobenzoic acid
- Sulfanilamide and p-aminobenzoic acid compete for the same active site of dihydropteroate synthase
Aspirin: Mode of Action
- Aspirin was developed from salicylic acid to reduce gastric irritation
- Aspirin confers its effect by inhibiting prostaglandin production
- John Vane's assay used strips of animal tissue to measure the contraction or relaxation of muscles in response to molecules like bradykinin, histamine, and ovalbumen
- Aspirin inhibits the production of prostaglandin E2 (PGE2) in the lungs
Aspirin Acetylation
- Aspirin acetylates biomolecules, with some specificity
- Incubating a biological sample with aspirin containing a radioactive acetyl group and running it on an SDS-PAGE gel can detect the acetylated protein
- The molecular weight of the peak is approximately 85,000 Da
Protein Polyacrylamide Gel Electrophoresis (PAGE)
- SDS-PAGE is used to separate and detect proteins based on their size and charge
- The protein is denatured and complexed with SDS, which conveys a negative charge and keeps the protein unfolded
- The sample is then subjected to an electric field, and the migration distance is proportional to the size of the protein
Initial Focus of Chem390
- The initial focus of Chem390 is on experiments and data interpretation, including experimental methods and qualitative and quantitative data interpretation.
- The course aims to build confidence in interpreting data, which is essential in real science, where the focus is not just on finding the correct answer, but also on how to figure it out.
Background and Prerequisites
- The course builds on previous material taught by Professors Sarojini and Barker.
- Students come from varied backgrounds, including MedChem, Biology, or MedSci, and some may have taken many biology classes but not some chemistry classes, while others may have taken chemistry classes but not biology classes.
Interpreting Data
- Interpreting standard errors (S.E. or S.E.M.) is important, and standard deviations and confidence intervals are different from standard errors.
- Understanding dose-response curves, including how to judge if a drug candidate is effective and how to determine the mechanism of action (MOA) of a medicine.
Ligand-Receptor Binding
- The behavior of [LP] can be described by the formula: [P] = [P]T - [LP].
- The dissociation constant (KD) can be calculated from a curve: KD = L [P] / [LP].
- Ligand-receptor binding curves can appear sigmoidal or hyperbolic, depending on the x-axis (linear vs logarithmic).
Enzyme Kinetics
- Enzyme kinetics are similar to receptor-ligand kinetics, with the equation: E + S ⇋ ES ⟶ E + P.
- The Michaelis-Menten (or Henri) equation is: V = Vmax [S] / (KM + [S]).
- Lineweaver-Burke plots can be used to analyze enzyme kinetics.
Enzyme Inhibition
- Enzyme inhibition can be competitive or non-competitive, and double-reciprocal plots can be used to determine the type of inhibition.
- Competitive inhibition plots on "normal" axes and double-reciprocal plots.
Determining the Mode of Action of a Medicine
- Determining the mode of action of a medicine is important because it helps to understand how the medicine works and to identify potential targets for new medicines.
- Molecular target-based and phenotype-based approaches can be used to determine the mode of action.
Historical Example: Sulfonamides
- Sulfonamides were the first widely-used antibacterials, and Prontosil was shown to be a prodrug in 1935.
- The mode of action of sulfanilamide was discovered by adding extra nutrients to bacteria, which made them withstand sulfanilamide better.
- The "Factor" in the yeast that protected against sulfanilamide was found to be para-aminobenzoic acid, which competes with sulfanilamide for the same active site.
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Description
This quiz explores the concept of determining the mode of action of a drug, including the use of molecular target-based and phenotype-based approaches. It also touches on the reversibility of naloxone binding.
