Questions and Answers
Which of the following is NOT a source of lead compounds for drug discovery?
What is a primary challenge with using peptides as lead compounds?
Which class of endogenous substances has been specifically mentioned as having served as lead compounds in drug discovery?
Which of the following endogenous compounds is specifically mentioned as related to Parkinson’s disease?
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Why can peptides usually not be delivered orally as lead compounds?
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What is a significant advantage of repurposed drugs compared to new drugs?
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What is required for a successful screening approach in drug discovery?
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Why might known ligands not be suitable starting points for drug discovery?
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Which one of the following is NOT mentioned as a type of drug in the context provided?
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What role do biological assays play in drug discovery?
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What is an example of a drug that has been repurposed for a different condition?
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Which statement about drug approval rates is accurate?
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What challenge is mentioned regarding endogenous ligands in drug discovery?
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What can significantly reduce the extent to which a drug is absorbed after oral administration?
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What is a primary feature of solid-phase library synthesis compared to solution-phase library synthesis?
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Which of the following steps is NOT typically involved in solution-phase library synthesis?
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Which method involves simultaneously treating multiple components in a microtiter plate?
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Which of the following factors does NOT influence a compound's bioavailability?
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What type of synthesis method allows for a few thousand compounds to be processed simultaneously?
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What is primarily involved in the reductive amination process occurring in solution-phase library synthesis?
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What is crucial for a compound to reach target tissues effectively after administration?
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What was a significant limitation of screening drugs using whole animals until 1980?
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Why have natural products been a valuable source of drug precursors?
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What does the construction of a screening library of structurally diverse compounds aim to achieve?
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What characteristic of small molecule natural products makes them an important area of research?
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What does pharmacokinetics refer to in drug discovery?
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Which statement is true regarding the potency of drug compounds in whole organisms?
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Why might synthetic drugs behave differently from natural products?
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What is a primary goal in the high-throughput screening (HTS) of compounds?
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Which route of administration is generally used when drugs absorb poorly when taken orally?
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What is the primary organ responsible for the metabolism of small-molecule drugs in the body?
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How does metabolism generally affect the parent drug once it enters the body?
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What negatively impacts the plasma concentration of a drug after systemic circulation?
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What is included in the ADME process related to drug administration?
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Which of the following is a potential site of drug excretion besides the kidneys?
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Which barrier poses a significant challenge for the distribution of certain drugs?
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What process describes the breakdown of a drug into metabolites?
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Study Notes
Lead Discovery in Drug Development
- Initiates the medicinal chemistry phase and is the second step in the drug discovery process.
- Focuses on identifying lead compounds, which serve as pivotal starting points for drug development.
Sources of Lead Compounds
- Endogenous Ligands: Substrates for enzymes, transporters, or natural agonists for receptors; important for diseases like Parkinson's and restless leg syndrome.
- Known Ligands: Existing marketed drugs can be repurposed, enhancing efficiency in drug development; repurposed drugs have higher success rates in clinical trials (25% for Phase I, 65% for Phase III).
- Compounds from Drug Metabolism Studies: Insights gained from the metabolism of drugs can yield potential leads.
- Clinical Trial Compounds: Drugs in clinical testing phases can provide leads.
- Chemical Libraries: Diversity in chemistry can be achieved through random or targeted library screening.
Endogenous Ligands in Lead Discovery
- Hormones and neurotransmitters (like serotonin) are key endogenous compounds used in drug discovery.
- Peptides present via hormone action are often limited by oral bioavailability due to metabolic instability.
Screening of Compounds
- Essential for discovering leads when endogenous ligands are unknown; biological assays measure the functional activity of candidate compounds.
- Modern methods include mass spectrometry, NMR, isothermal calorimetry, and fluorescent polarization.
- Traditional methods involved whole organisms or animals, which can introduce variability in pharmacodynamics and pharmacokinetics.
Natural Products
- Natural products have historically contributed to over 60% of anticancer and anti-infective drugs marketed from 1981-2006.
- Secondary metabolites often evolve as defense mechanisms, influencing drug design opportunities.
Screening Library Construction
- Diversity in compound libraries is critical since structurally diverse compounds can yield varied biological activities.
- High-Throughput Screening (HTS) offers efficient means for evaluating large libraries of compounds.
Solid-Phase and Solution-Phase Library Synthesis
- Solid-Phase Synthesis: Enables the creation of diverse compound libraries, with notable examples including hydroxy benzodiazepines and proline derivatives.
- Solution-Phase Synthesis: Allows parallel processing of compounds; can synthesize thousands of compounds simultaneously in microtiter plates.
ADME (Absorption, Distribution, Metabolism, Excretion)
- Absorption: Drug must enter systemic circulation; influenced by factors such as solubility and intestinal permeability.
- Distribution: Process of drug dispersal throughout the body; affected by blood flow, molecular size, and protein binding; can be hindered by barriers like the blood–brain barrier.
- Metabolism: Primarily occurs in the liver through cytochrome P450 enzymes, which convert parent drugs into active or inactive metabolites.
- Excretion: Removal of drugs/metabolites from the body via kidneys (urine), feces, or lungs; critically affected by the drug's route of administration.
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Description
Explore the critical phase of lead discovery in medicinal chemistry, which is the second step in drug development. This quiz examines the various sources of lead compounds such as endogenous ligands, marketed drugs, and compounds from clinical trials. Test your knowledge and enhance your understanding of the drug discovery process.
