Medicinal Chemistry: Lead Discovery

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Questions and Answers

Which of the following is NOT a source of lead compounds for drug discovery?

Chemical libraries

Endogenous ligands

Compounds used in clinical trials

Lifestyle changes (correct)

What is a primary challenge with using peptides as lead compounds?

Excessive bioavailability

Overdependence on external sources

Instability to gut peptidases (correct)

High cost of synthesis

Which class of endogenous substances has been specifically mentioned as having served as lead compounds in drug discovery?

Hormones (correct)

Synthetic polymers

Pathogens

Minerals

Which of the following endogenous compounds is specifically mentioned as related to Parkinson’s disease?

Neurotransmitters Signup and view all the answers

Why can peptides usually not be delivered orally as lead compounds?

Low permeability across gut membranes Signup and view all the answers

What is a significant advantage of repurposed drugs compared to new drugs?

Higher rates of approval in clinical trials Signup and view all the answers

What is required for a successful screening approach in drug discovery?

A method to assay compounds for biological activity Signup and view all the answers

Why might known ligands not be suitable starting points for drug discovery?

They may not have desired properties Signup and view all the answers

Which one of the following is NOT mentioned as a type of drug in the context provided?

Antiviral Signup and view all the answers

What role do biological assays play in drug discovery?

They measure the functional activity of molecules Signup and view all the answers

What is an example of a drug that has been repurposed for a different condition?

An antidepressant for chronic lower back pain Signup and view all the answers

Which statement about drug approval rates is accurate?

More than 50% of new drugs fail in Phase III trials Signup and view all the answers

What challenge is mentioned regarding endogenous ligands in drug discovery?

They may not be known for a target of interest Signup and view all the answers

What can significantly reduce the extent to which a drug is absorbed after oral administration?

Inability to permeate the intestinal wall Signup and view all the answers

What is a primary feature of solid-phase library synthesis compared to solution-phase library synthesis?

More effective at creating discrete compounds Signup and view all the answers

Which of the following steps is NOT typically involved in solution-phase library synthesis?

Filtration of solid-phase resins Signup and view all the answers

Which method involves simultaneously treating multiple components in a microtiter plate?

Parallel library synthesis Signup and view all the answers

Which of the following factors does NOT influence a compound's bioavailability?

Radiological imaging Signup and view all the answers

What type of synthesis method allows for a few thousand compounds to be processed simultaneously?

Solution-phase library synthesis Signup and view all the answers

What is primarily involved in the reductive amination process occurring in solution-phase library synthesis?

Formation of aminomethyl derivatives Signup and view all the answers

What is crucial for a compound to reach target tissues effectively after administration?

It must enter systemic circulation Signup and view all the answers

What was a significant limitation of screening drugs using whole animals until 1980?

Results depended on various factors apart from the compound's potency. Signup and view all the answers

Why have natural products been a valuable source of drug precursors?

More than 60% of marketed anticancer agents are derived from them. Signup and view all the answers

What does the construction of a screening library of structurally diverse compounds aim to achieve?

To allow for divergent biological activities from a variety of structures. Signup and view all the answers

What characteristic of small molecule natural products makes them an important area of research?

They tend to target essential proteins of coevolved organisms. Signup and view all the answers

What does pharmacokinetics refer to in drug discovery?

The absorption, distribution, metabolism, and excretion of the compound. Signup and view all the answers

Which statement is true regarding the potency of drug compounds in whole organisms?

Results may vary due to biological factors besides potency. Signup and view all the answers

Why might synthetic drugs behave differently from natural products?

Synthetic drugs are designed to target human diseases, unlike natural products. Signup and view all the answers

What is a primary goal in the high-throughput screening (HTS) of compounds?

To create a library that captures a wide range of biological activities. Signup and view all the answers

Which route of administration is generally used when drugs absorb poorly when taken orally?

By inhalation Signup and view all the answers

What is the primary organ responsible for the metabolism of small-molecule drugs in the body?

Liver Signup and view all the answers

How does metabolism generally affect the parent drug once it enters the body?

It often converts it into pharmacologically inert metabolites. Signup and view all the answers

What negatively impacts the plasma concentration of a drug after systemic circulation?

Regional blood flow rates Signup and view all the answers

What is included in the ADME process related to drug administration?

Absorption, Distribution, Metabolism, Excretion Signup and view all the answers

Which of the following is a potential site of drug excretion besides the kidneys?

Intestines Signup and view all the answers

Which barrier poses a significant challenge for the distribution of certain drugs?

Blood-brain barrier Signup and view all the answers

What process describes the breakdown of a drug into metabolites?

Metabolism Signup and view all the answers

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.