Podcast
Questions and Answers
What is the primary mechanism through which successful antagonists typically bind to their targets?
What is the primary mechanism through which successful antagonists typically bind to their targets?
Which ion channel blockade is associated with prolongation of the cardiac Q-T interval?
Which ion channel blockade is associated with prolongation of the cardiac Q-T interval?
What differentiates agonists from antagonists in pharmacological terms?
What differentiates agonists from antagonists in pharmacological terms?
Which of the following statements is true about ion channels?
Which of the following statements is true about ion channels?
Signup and view all the answers
Which of the following drugs emerged from calcium-channel antagonist programs?
Which of the following drugs emerged from calcium-channel antagonist programs?
Signup and view all the answers
What type of inhibition involves an inhibitor binding only to the enzyme-substrate (ES) complex?
What type of inhibition involves an inhibitor binding only to the enzyme-substrate (ES) complex?
Signup and view all the answers
Which inhibition type allows partially inhibited enzymes to still turn over substrate?
Which inhibition type allows partially inhibited enzymes to still turn over substrate?
Signup and view all the answers
Which of the following is a characteristic of irreversible inhibition?
Which of the following is a characteristic of irreversible inhibition?
Signup and view all the answers
What is the main function of proteases?
What is the main function of proteases?
Signup and view all the answers
Endopeptidases have cleavage sites that can be located where in the substrate?
Endopeptidases have cleavage sites that can be located where in the substrate?
Signup and view all the answers
Which statement correctly describes the specificity of proteases?
Which statement correctly describes the specificity of proteases?
Signup and view all the answers
Which of the following is an example of irreversible inhibition?
Which of the following is an example of irreversible inhibition?
Signup and view all the answers
What is the primary role of allosteric inhibitors in non-competitive inhibition?
What is the primary role of allosteric inhibitors in non-competitive inhibition?
Signup and view all the answers
Which of the following protease classes specifically uses water as a nucleophile and prefers a pH of 3-6?
Which of the following protease classes specifically uses water as a nucleophile and prefers a pH of 3-6?
Signup and view all the answers
What binds to the active site machinery in irreversible inhibition likely resulting in what is known as suicide inhibition?
What binds to the active site machinery in irreversible inhibition likely resulting in what is known as suicide inhibition?
Signup and view all the answers
What is the role of the catalytic triad in serine proteases?
What is the role of the catalytic triad in serine proteases?
Signup and view all the answers
Which of the following describes the action of agonists at receptors?
Which of the following describes the action of agonists at receptors?
Signup and view all the answers
What characterizes the majority of known receptors?
What characterizes the majority of known receptors?
Signup and view all the answers
Which type of ligand induces no signal when bound to a receptor?
Which type of ligand induces no signal when bound to a receptor?
Signup and view all the answers
What is the significance of the P1 site in serine proteases?
What is the significance of the P1 site in serine proteases?
Signup and view all the answers
What happens when an excited-state receptor is activated?
What happens when an excited-state receptor is activated?
Signup and view all the answers
What do inhibitors of serine proteases typically do?
What do inhibitors of serine proteases typically do?
Signup and view all the answers
In the context of GPCRs, what role do the intracellular loops play?
In the context of GPCRs, what role do the intracellular loops play?
Signup and view all the answers
Which of the following is NOT a characteristic of receptors?
Which of the following is NOT a characteristic of receptors?
Signup and view all the answers
Which of the following is true about thrombin and chymotrypsin?
Which of the following is true about thrombin and chymotrypsin?
Signup and view all the answers
What is the primary purpose of High Throughput Screening (HTS) in the drug discovery process?
What is the primary purpose of High Throughput Screening (HTS) in the drug discovery process?
Signup and view all the answers
Which category of enzyme inhibitors works by altering the enzyme's active site directly?
Which category of enzyme inhibitors works by altering the enzyme's active site directly?
Signup and view all the answers
What is a common characteristic of partial agonists?
What is a common characteristic of partial agonists?
Signup and view all the answers
In the drug discovery process, how long does the Hit-to-Lead (HtL) phase typically take?
In the drug discovery process, how long does the Hit-to-Lead (HtL) phase typically take?
Signup and view all the answers
What type of drug is Lipitor and what is its primary mechanism?
What type of drug is Lipitor and what is its primary mechanism?
Signup and view all the answers
What does the 'Lead Optimization' phase in drug development focus on?
What does the 'Lead Optimization' phase in drug development focus on?
Signup and view all the answers
What type of inhibitors binds to sites other than the active site?
What type of inhibitors binds to sites other than the active site?
Signup and view all the answers
Which class of biological mechanisms do ion channel blockers fall into?
Which class of biological mechanisms do ion channel blockers fall into?
Signup and view all the answers
What is the main function of the active site in an enzyme?
What is the main function of the active site in an enzyme?
Signup and view all the answers
What characterizes inverse agonists in relation to receptor activity?
What characterizes inverse agonists in relation to receptor activity?
Signup and view all the answers
What is the significance of Free Energy in enzyme reactions?
What is the significance of Free Energy in enzyme reactions?
Signup and view all the answers
Which type of biological mechanism typically involves interaction between two proteins?
Which type of biological mechanism typically involves interaction between two proteins?
Signup and view all the answers
What duration does candidate drug development typically take following lead optimization?
What duration does candidate drug development typically take following lead optimization?
Signup and view all the answers
What does the acronym 'CD' refer to in the context of the drug discovery process?
What does the acronym 'CD' refer to in the context of the drug discovery process?
Signup and view all the answers
Study Notes
Advanced Medicinal Chemistry Lecture 1: Target Classes
- Drug Discovery Process: A diagram illustrates the stages involved in discovering drugs, ranging from Target Identification to Candidate Drug (CD) development.
- Timeframes: Various stages have different time allotments. Target Identification spans 3 months to 2 years. HTS (High-Throughput Screening) takes 3-4 months. Active-to-Hit (AtH) takes 3 months. Hit-to-Lead (HtL) takes 6-9 months. New Lead Optimisation Projects (LO) take 2 years to develop into a Candidate Drug (CD).
Taxonomy of Biological Mechanisms
- In vivo Effectors: A branching diagram demonstrates how different biological mechanisms, relating to receptors, enzymes, ion channels and protein-protein interactions, can be categorized by their roles in various biological processes within a living organism ("in vivo").
- Receptors: Receptors can be agonists, antagonists, partial agonists or inverse agonists.
- Enzymes: Enzymes can be inhibitors.
- Ion Channels: Ion channels can be openers or blockers.
- Protein-Protein Interactions: Protein-protein interactions can be inhibitors.
Blockbuster Drugs
- Lipitor: An HMG CoA inhibitor, made by Pfizer, costs $12 billion.
- Plavix: An anti-platelet, made by BMS/Sanofi-Aventis, costs $5 billion.
- Nexium: A proton pump inhibitor, made by AstraZeneca, costs $4.8 billion.
- Norvasc: A calcium channel blocker, made by Pfizer, costs $4.8 billion.
- Drugs Mechanism and Types: The diagram shows different types of drugs (such as enzyme or receptor based), and chemical representations of example blockbuster drugs.
Biological Mechanisms (2005)
- Top 50 Drugs by Sales: A pie chart illustrates the distribution of top 50 drugs by mechanism in 2005 categorized by Receptor Antagonist, Enzyme inhibitor, Receptor agonist, Miscellaneous, Biological Modulator, and Ion Channel Modulator.
- Enzyme Function: A diagram shows how enzymes use an active site to bind a transition state during a reaction. It also explains the concept of allosteric binding, which occurs away from the active site.
Enzyme Inhibition
- Four Mechanistic Categories: Four types of enzyme inhibition are listed: competitive, uncompetitive, non-competitive (also called allosteric), and irreversible.
- Inhibitors: In competitive inhibition, inhibitors compete with the substrate for the active site, while in uncompetitive inhibition, inhibitors bind to the enzyme-substrate complex. Non-competitive inhibitors bind at a place other than the active site (allosteric). Irreversible inhibitors bind covalently to the enzyme, inhibiting its function permanently.
Proteases
- Hydrolytic Action: Proteases (proteinases, peptidases) hydrolytically cleave peptidic amide bonds between amino acids in proteins.
- Classes and Characteristics: This includes four classes: serine (ser), cysteine (thiol), aspartic and zinc-based proteases. Different classes have different nucleophiles ("e.g., ser-CH2OH" or "cys-CH2SH") and associated pH preference ranges. Some proteases can act on the inner part of a polypeptide chain (endo) while others only act at the ends (exo).
Protease Specificity
- Side-Chain Binding: Protease specificity is determined by how amino acid side-chains near the cleavage site of a polypeptide bind to the enzyme. The diagram shows the nomenclature used to describe these binding sites (Specificity pockets, or P1 to P3).
Serine Proteases
- Catalytic Triad: A serine protease's catalytic activity depends on a catalytic triad composed of Asp, His, and Ser amino acids.
- Oxyanion Hole: The oxyanion hole is critical for stabilizing the transition state during the reaction.
Receptors
- Membrane-Bound Proteins: Receptors are membrane-bound proteins that bind endogenous ligands, often outside the cell to initiate signal transduction inside the cell.
- G-Protein Coupled Receptors: G-protein coupled receptors (GPCRs) are frequently associated with important physiological cascades.
- Seven Transmembrane Spanning: Seven transmembrane spanning receptors (7TM) structure is detailed.
Binding to Receptors
- Agonist vs. Antagonist: Agonists bind to a receptor, triggering a conformational change resulting in a signal. Antagonists bind, inducing no signal, preventing agonists from binding. Ligands might be small molecules, proteins or peptides.
- Competitive Binding: Agonists and antagonists bind competitively to receptors.
- Binding Characteristics: Endogenous agonists often bind weakly, while successful antagonists often bind tightly.
Ion Channels
- Membrane Potential: Living cells have an essential electrical potential difference across their membranes (60-70 mV).
- Passive Ion Flow: Ion channels regulate passive ion flow across cellular membranes based on electric fields and concentration gradients.
- Structure and Function: Ion channels are proteins with specific ion selectivity.
- Involved Mechanisms: They are key regulators in cardiac, neuronal, and other vital physiological processes.
- Various Types: Ion channels can be categorized as voltage-gated or ligand-gated.
- Ligands: Ligands that act on ion channels can be other ions, small molecules, or toxins.
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Related Documents
Description
Explore the intricacies of drug discovery in this detailed lecture. From target identification to candidate drug development, learn about the timeframes involved and the biological mechanisms underpinning drug efficacy. This foundational knowledge sets the stage for understanding medicinal chemistry on a deeper level.
