Podcast
Questions and Answers
What is the primary benefit of High Throughput Screening (HTS) in drug discovery?
What is the primary benefit of High Throughput Screening (HTS) in drug discovery?
Which of the following statements about Cialis is true?
Which of the following statements about Cialis is true?
What percentage of new drug projects are estimated to originate from High Throughput Screening?
What percentage of new drug projects are estimated to originate from High Throughput Screening?
Which statement best describes the impact of HTS on drug development?
Which statement best describes the impact of HTS on drug development?
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What advantage is often associated with Levitra compared to other drugs?
What advantage is often associated with Levitra compared to other drugs?
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What is the time duration for the Active-to-Hit (AtH) phase in the drug discovery process?
What is the time duration for the Active-to-Hit (AtH) phase in the drug discovery process?
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Which source is NOT mentioned as a lead compound source?
Which source is NOT mentioned as a lead compound source?
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How long does the Hit-to-Lead (HtL) process typically take?
How long does the Hit-to-Lead (HtL) process typically take?
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What is the initial phase in the drug discovery process that involves Target Identification?
What is the initial phase in the drug discovery process that involves Target Identification?
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Which compound is cited as an example of a natural product lead compound?
Which compound is cited as an example of a natural product lead compound?
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What is the total estimated time required to develop a new lead after the drug discovery process phases?
What is the total estimated time required to develop a new lead after the drug discovery process phases?
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What is involved in the final stages of lead optimization?
What is involved in the final stages of lead optimization?
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Which of the following phases follows the Hit-to-Lead phase directly?
Which of the following phases follows the Hit-to-Lead phase directly?
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Which drug is associated with the company AstraZeneca?
Which drug is associated with the company AstraZeneca?
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What is a common issue associated with existing drugs mentioned in the content?
What is a common issue associated with existing drugs mentioned in the content?
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What does the term 'bioisostere' refer to in the context of catechol?
What does the term 'bioisostere' refer to in the context of catechol?
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Which of the following compounds is associated with the increased toxicity mentioned?
Which of the following compounds is associated with the increased toxicity mentioned?
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What does the 'Me-Too' or 'Me-Better' approach refer to?
What does the 'Me-Too' or 'Me-Better' approach refer to?
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Which company is associated with the drug Salbutamol?
Which company is associated with the drug Salbutamol?
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What potential issue does Viagra face in its usage?
What potential issue does Viagra face in its usage?
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What structural feature of catechol may lead to increased selectivity?
What structural feature of catechol may lead to increased selectivity?
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What is the primary purpose of High Throughput Screening (HTS) technologies?
What is the primary purpose of High Throughput Screening (HTS) technologies?
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Which of the following is a characteristic benefit of Scintillation Proximity Assay (SPA)?
Which of the following is a characteristic benefit of Scintillation Proximity Assay (SPA)?
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What is a common limitation of SPA?
What is a common limitation of SPA?
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What is the primary financial allocation for the acquisition theme?
What is the primary financial allocation for the acquisition theme?
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Which of the following reactions is NOT listed as a common combinatorial reaction?
Which of the following reactions is NOT listed as a common combinatorial reaction?
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FLIPR technology is most commonly used for which type of assays?
FLIPR technology is most commonly used for which type of assays?
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What does a validated and tractable target in HTS refer to?
What does a validated and tractable target in HTS refer to?
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What is a primary focus aligned with the synthesis theme?
What is a primary focus aligned with the synthesis theme?
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Which problem is associated with compound screening in HTS?
Which problem is associated with compound screening in HTS?
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In terms of CCE structure, which site is associated with bioscience?
In terms of CCE structure, which site is associated with bioscience?
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How does the throughput of SPA compare to other screening methods?
How does the throughput of SPA compare to other screening methods?
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Which of the following types of chemistry is emphasized within the CCE framework?
Which of the following types of chemistry is emphasized within the CCE framework?
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What is one of the benefits of chemistry being embedded in research areas?
What is one of the benefits of chemistry being embedded in research areas?
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What is the purpose of the AstraZeneca global initiative for compound collection enhancement?
What is the purpose of the AstraZeneca global initiative for compound collection enhancement?
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Which class of compounds does NOT appear in the list of reactions provided?
Which class of compounds does NOT appear in the list of reactions provided?
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What is a significant advantage of using 1536 well plates in HTS?
What is a significant advantage of using 1536 well plates in HTS?
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What is one of the primary uses of HTS assay technologies?
What is one of the primary uses of HTS assay technologies?
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Which reaction involves the formation of sulphonamide?
Which reaction involves the formation of sulphonamide?
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Which of the following correctly describes one of the patterns of types of reactions?
Which of the following correctly describes one of the patterns of types of reactions?
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What is the significance of having validated targets in the context of HTS?
What is the significance of having validated targets in the context of HTS?
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What caution is advised regarding fluorescence-based HTS methods?
What caution is advised regarding fluorescence-based HTS methods?
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What type of coupling is primarily involved in creating complex organic molecules?
What type of coupling is primarily involved in creating complex organic molecules?
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What is one key differing factor between HTS and traditional screening methods?
What is one key differing factor between HTS and traditional screening methods?
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How many scientists are approximately involved in the research areas as indicated?
How many scientists are approximately involved in the research areas as indicated?
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What is the role of big Medchem input in the acquisition theme?
What is the role of big Medchem input in the acquisition theme?
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What is one of the types of reactions that includes multiple components?
What is one of the types of reactions that includes multiple components?
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Which synthesis compound is associated with the reaction type of reductive amination?
Which synthesis compound is associated with the reaction type of reductive amination?
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Flashcards
Drug Discovery Process
Drug Discovery Process
A multi-step process from target identification to candidate drug development.
Lead Compound Sources
Lead Compound Sources
Lead compounds can originate from chance discoveries, natural products, clinical observations, and more.
Chance Discovery
Chance Discovery
Discovering new lead compounds through unintended or unplanned observations.
Natural Products
Natural Products
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Clinical Observation
Clinical Observation
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Active-to-Hit (AtH)
Active-to-Hit (AtH)
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Hit-to-Lead (HtL)
Hit-to-Lead (HtL)
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New Lead Optimisation (LO)
New Lead Optimisation (LO)
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Natural Ligands
Natural Ligands
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Existing Drugs (Me-Too/Me-Better approach)
Existing Drugs (Me-Too/Me-Better approach)
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High Throughput Screening (HTS)
High Throughput Screening (HTS)
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Bioisostere
Bioisostere
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Catechol
Catechol
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Viagra
Viagra
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Patent Issues
Patent Issues
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Formoterol/Salbutamol
Formoterol/Salbutamol
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Lead Compound
Lead Compound
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Target
Target
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Tractable Target
Tractable Target
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What proportion of new drug projects come from HTS?
What proportion of new drug projects come from HTS?
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What makes a good HTS target?
What makes a good HTS target?
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HTS assay technologies
HTS assay technologies
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Microtiter plates: HTS workhorses
Microtiter plates: HTS workhorses
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Scintillation Proximity Assay (SPA)
Scintillation Proximity Assay (SPA)
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FLIPR: A high-throughput fluorimeter
FLIPR: A high-throughput fluorimeter
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Compound collection for HTS
Compound collection for HTS
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Why is a diverse compound collection important for HTS?
Why is a diverse compound collection important for HTS?
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What are some challenges with compound collections?
What are some challenges with compound collections?
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What is the goal of compound collection enhancement?
What is the goal of compound collection enhancement?
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How does redundancy affect HTS?
How does redundancy affect HTS?
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Why is chemical diversity important for HTS success?
Why is chemical diversity important for HTS success?
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How can HTS technology help drug discovery?
How can HTS technology help drug discovery?
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Why is Automation important for HTS?
Why is Automation important for HTS?
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What are some benefits of using HTS technologies in drug discovery?
What are some benefits of using HTS technologies in drug discovery?
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What are some challenges associated with HTS?
What are some challenges associated with HTS?
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CCE Structure
CCE Structure
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CCE - Library Chemistry
CCE - Library Chemistry
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Most Common CCE Reactions
Most Common CCE Reactions
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Amide Coupling
Amide Coupling
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Sulphonamide Formation
Sulphonamide Formation
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Reductive Amination
Reductive Amination
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Amide Coupling Mechanism
Amide Coupling Mechanism
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Sulphonamide Formation Mechanism
Sulphonamide Formation Mechanism
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Reductive Amination Mechanism
Reductive Amination Mechanism
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HTS (High-Throughput Screening)
HTS (High-Throughput Screening)
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CCE - Central Bioscience
CCE - Central Bioscience
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CCE - Med Chem
CCE - Med Chem
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CCE - Cheminformatics
CCE - Cheminformatics
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CCE - Comp Chem
CCE - Comp Chem
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CCE - Informatics
CCE - Informatics
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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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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.