Advanced Medicinal Chemistry - Lecture 2
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What is the primary benefit of High Throughput Screening (HTS) in drug discovery?

  • It reduces the number of targets available for drug discovery.
  • It provides a slower, more methodical approach to finding drugs.
  • It rapidly identifies novel lead compounds from chemical diversity. (correct)
  • It increases the cost of drug development significantly.

    • Which of the following statements about Cialis is true?

  • Cialis is often referred to as 'the weekend pill.' (correct)
  • Cialis has a duration of approximately 12 hours.
  • Cialis causes more side effects compared to Levitra.
  • Cialis is also known as 'the morning after pill.'

    • What percentage of new drug projects are estimated to originate from High Throughput Screening?

  • 30-50%
  • Less than 10%
  • 50-70% (correct)
  • Over 90%

    • Which statement best describes the impact of HTS on drug development?

    <p>HTS streamlines the initial stages of drug discovery.</p> Signup and view all the answers

    What advantage is often associated with Levitra compared to other drugs?

    <p>It has fewer side effects and drug incompatibilities.</p> Signup and view all the answers

    What is the time duration for the Active-to-Hit (AtH) phase in the drug discovery process?

    <p>3 months</p> Signup and view all the answers

    Which source is NOT mentioned as a lead compound source?

    <p>Synthetic Chemistry</p> Signup and view all the answers

    How long does the Hit-to-Lead (HtL) process typically take?

    <p>6-9 months</p> Signup and view all the answers

    What is the initial phase in the drug discovery process that involves Target Identification?

    <p>2 years</p> Signup and view all the answers

    Which compound is cited as an example of a natural product lead compound?

    <p>Taxol</p> Signup and view all the answers

    What is the total estimated time required to develop a new lead after the drug discovery process phases?

    <p>3 years</p> Signup and view all the answers

    What is involved in the final stages of lead optimization?

    <p>New Lead Optimization Projects</p> Signup and view all the answers

    Which of the following phases follows the Hit-to-Lead phase directly?

    <p>New Lead Optimization</p> Signup and view all the answers

    Which drug is associated with the company AstraZeneca?

    <p>Formoterol</p> Signup and view all the answers

    What is a common issue associated with existing drugs mentioned in the content?

    <p>Short duration and side effects</p> Signup and view all the answers

    What does the term 'bioisostere' refer to in the context of catechol?

    <p>An increased size that enhances selectivity</p> Signup and view all the answers

    Which of the following compounds is associated with the increased toxicity mentioned?

    <p>Catechol bioisostere</p> Signup and view all the answers

    What does the 'Me-Too' or 'Me-Better' approach refer to?

    <p>Modifying existing drugs for improvement</p> Signup and view all the answers

    Which company is associated with the drug Salbutamol?

    <p>GlaxoSmithKline</p> Signup and view all the answers

    What potential issue does Viagra face in its usage?

    <p>Incompatibility with other drugs</p> Signup and view all the answers

    What structural feature of catechol may lead to increased selectivity?

    <p>Increased size of the compound</p> Signup and view all the answers

    What is the primary purpose of High Throughput Screening (HTS) technologies?

    <p>To identify and select potential compounds for drug development</p> Signup and view all the answers

    Which of the following is a characteristic benefit of Scintillation Proximity Assay (SPA)?

    <p>Allows for automation with minimal aqueous waste</p> Signup and view all the answers

    What is a common limitation of SPA?

    <p>Long read times and safety concerns due to radioactive materials</p> Signup and view all the answers

    What is the primary financial allocation for the acquisition theme?

    <p>300K from 107 available</p> Signup and view all the answers

    Which of the following reactions is NOT listed as a common combinatorial reaction?

    <p>Methylation</p> Signup and view all the answers

    FLIPR technology is most commonly used for which type of assays?

    <p>Kinetic analysis of whole cells during ion channel screening</p> Signup and view all the answers

    What does a validated and tractable target in HTS refer to?

    <p>A target that can yield reliable and actionable results in screening</p> Signup and view all the answers

    What is a primary focus aligned with the synthesis theme?

    <p>Target-class focus</p> Signup and view all the answers

    Which problem is associated with compound screening in HTS?

    <p>Inadequate chemical diversity in compound libraries</p> Signup and view all the answers

    In terms of CCE structure, which site is associated with bioscience?

    <p>Mölndal</p> Signup and view all the answers

    How does the throughput of SPA compare to other screening methods?

    <p>SPA can screen approximately 30K compounds per day in a 384 format</p> Signup and view all the answers

    Which of the following types of chemistry is emphasized within the CCE framework?

    <p>Project Focused Chemistry</p> Signup and view all the answers

    What is one of the benefits of chemistry being embedded in research areas?

    <p>Enhances parallel synthesis skills</p> Signup and view all the answers

    What is the purpose of the AstraZeneca global initiative for compound collection enhancement?

    <p>Ensure viable hits from 75% of AZ HTS</p> Signup and view all the answers

    Which class of compounds does NOT appear in the list of reactions provided?

    <p>Imidazoles</p> Signup and view all the answers

    What is a significant advantage of using 1536 well plates in HTS?

    <p>Higher density increases the number of compounds tested simultaneously</p> Signup and view all the answers

    What is one of the primary uses of HTS assay technologies?

    <p>Simultaneously testing large numbers of compounds</p> Signup and view all the answers

    Which reaction involves the formation of sulphonamide?

    <p>Sulphonamide Formation</p> Signup and view all the answers

    Which of the following correctly describes one of the patterns of types of reactions?

    <p>Cyclization to Heterocycles and Acyl Sulphonamide Formation</p> Signup and view all the answers

    What is the significance of having validated targets in the context of HTS?

    <p>It indicates that the elucidated targets have a high likelihood of being actionable</p> Signup and view all the answers

    What caution is advised regarding fluorescence-based HTS methods?

    <p>They can produce misleading results from intensity variations</p> Signup and view all the answers

    What type of coupling is primarily involved in creating complex organic molecules?

    <p>Amide Coupling</p> Signup and view all the answers

    What is one key differing factor between HTS and traditional screening methods?

    <p>HTS allows for simultaneous processing of multiple samples</p> Signup and view all the answers

    How many scientists are approximately involved in the research areas as indicated?

    <p>60 Scientists</p> Signup and view all the answers

    What is the role of big Medchem input in the acquisition theme?

    <p>Filter input</p> Signup and view all the answers

    What is one of the types of reactions that includes multiple components?

    <p>Multicomponent Reaction</p> Signup and view all the answers

    Which synthesis compound is associated with the reaction type of reductive amination?

    <p>Aminopyrazoles</p> Signup and view all the answers

    Study Notes

    Advanced Medicinal Chemistry - Lecture 2: Finding a Lead

    • Drug Discovery Process: A flowchart outlines the stages, highlighting timeframes for each step:
      • Target Identification (3 months to 2 years)
      • High Throughput Screening (HTS) (3-4 months)
      • Active-to-Hit (AtH) (3 months)
      • Hit-to-Lead (HtL) (6-9 months)
      • New Lead Optimisation Projects (LO) (2 years)
      • Candidate Drug (CD) (2 years)

    Lead Compound Sources

    • Chance Discovery: Leads identified unexpectedly, an example being the discovery of penicillin.
    • Natural Products: Leads derived from natural sources, such as taxol from the Pacific yew tree.
    • Clinical Observation: Leads discovered through studying a patient's condition and response to different treatments.
    • Natural Ligands: Molecules naturally occurring in the body, such as adrenaline and noradrenaline, forms the basis of medicines that mimic these effects. Bioisosteres are used as replacements for such natural ligands to create new molecules with similar effects but potentially lower toxicity.
    • Existing Drugs: Modifying existing drugs to create new ones targeting different diseases, or with improved efficacy, safety or usage profile. Examples in the presentation were Viagra, Cialis and Levitra.
    • High Throughput Screening (HTS): A method that screens large numbers of compounds to rapidly identify leads against a target protein or pathway.

    High Throughput Screening (HTS)

    • Definition: A method to rapidly identify novel lead compounds for drug discovery, accounting for 50-70% of new projects.
    • Methodology:
      • Validated and tractable targets are selected.
      • An industrialised process utilises advanced technologies.
      • HTS assays and automation are used, alongside chemical diversity in compounds.
      • Selecting the correct sample library is crucial.
    • Establishing HTS:
      • Defining target proteins/pathways for investigation.
      • Identifying a suitable range of chemical compounds.
    • Microtitre Plates: Provide the mechanism for HTS, using various sizes and formats of such plates.

    HTS Technologies

    • Charnwood HTS Technologies (1995-2001): Provides detail of different methods used and their relative significance including:
      • SPA (Scintillation Proximity Assay): A homogenous technology that allows throughput (~30K compounds/day in 384 format) with ease of automation. but is dependent on radioactive compounds and susceptible to quench artifacts.
      • FLIPR (Fluorescent Imaging Plate Reader): A real-time imaging technology used to monitor cellular activity and kinetic based assays (e.g. Ca2+ flux assays and ion channel screening)

    AstraZeneca Compound Collection

    • Development: AstraZeneca uses multiple acquisition and synthesis strategies.
    • Structure: The collection is distributed across different centres (e.g., Charnwood, Mölndal, Alderly Park).
    • Overlap: Significant compound overlap exists between different parts of the collection (~9%). This accounts for significant redundancy.
    • Enhancement (CCE): A project aiming to improve the current collections.
      • Acquisition: 300,000 existing compounds are sourced from over 10 million possible compounds. Big pharmaceutical input and stringent filters to remove unsuitable compounds.
      • Synthesis: 500,000 new compounds are synthesized throughout 5 years. Targeting specific biological pathways and using advanced methodologies such as aligned research areas and bioscience.

    CCE Structure and Chemistry

    • Structure and Chemistry: The CCE focuses on strategically placing chemistry within research areas for optimal utilisation of resources. 
    • Reactions: Commonly used combinatorial reactions include amide coupling, reductive amination and sulfonamide formation.

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    Advanced Medicinal Chemistry Lecture 2: Finding a Lead PDF

    Description

    Dive into Lecture 2 of Advanced Medicinal Chemistry, focusing on the drug discovery process and the various sources of lead compounds. Understand the timelines associated with each stage of discovery and the significance of chance findings, natural products, and clinical observations in developing new drugs.

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