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Questions and Answers
What is the name of the first stage of the drug discovery process?
What is the name of the first stage of the drug discovery process?
Target Identification
What are the four main mechanistic categories of enzyme inhibition?
What are the four main mechanistic categories of enzyme inhibition?
What is the name of the process when an inhibitor binds non-covalently to sites other than the active site of an enzyme?
What is the name of the process when an inhibitor binds non-covalently to sites other than the active site of an enzyme?
Allosteric Inhibition
Irreversible inhibition occurs when an inhibitor binds covalently to the active site of an enzyme.
Irreversible inhibition occurs when an inhibitor binds covalently to the active site of an enzyme.
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The active site of an enzyme is tailored to bind the ______ state of the substrate for S->P
The active site of an enzyme is tailored to bind the ______ state of the substrate for S->P
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What are the four mechanistic classes of proteases?
What are the four mechanistic classes of proteases?
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What type of inhibitor is typically used to target serine proteases?
What type of inhibitor is typically used to target serine proteases?
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What type of receptor is responsible for the majority of known examples of receptors?
What type of receptor is responsible for the majority of known examples of receptors?
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Endogenous agonists often bind weakly to receptors.
Endogenous agonists often bind weakly to receptors.
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Which of the following ions are involved in ion channels?
Which of the following ions are involved in ion channels?
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What is the name of the ion channel that is responsible for the prolongation of cardiac Q-T interval?
What is the name of the ion channel that is responsible for the prolongation of cardiac Q-T interval?
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Ligands can include other ions, small molecules, toxins, and venoms.
Ligands can include other ions, small molecules, toxins, and venoms.
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What is the class of blockbuster antihypertensive drugs that have emerged from calcium channel antagonist programmes?
What is the class of blockbuster antihypertensive drugs that have emerged from calcium channel antagonist programmes?
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What are the two main classes of ion channels?
What are the two main classes of ion channels?
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Study Notes
Advanced Medicinal Chemistry - Lecture 1: Target Classes
- The lecture is about target classes in advanced medicinal chemistry.
- The drug discovery process has stages: target identification (3-24 months), HTS (3-4 months), Active-to-Hit (AtH) ( 3 months), Hit-to-Lead (HtL) (6-9 months), New Lead Optimisation Projects (LO) (2 years), and Candidate Drug (CD) (2 years).
- Biological mechanisms include receptors (agonists, antagonists, partial agonists, inverse agonists), enzymes (inhibitors), ion channels (openers, blockers), and protein-protein inhibitors.
- Effective drugs, such as Lipitor (HMG CoA inhibitor, $12 billion), Plavix (anti-platelet, $5 billion), Nexium (proton pump inhibitor, $4.8 billion), and Norvasc (calcium channel blocker, $4.8 billion) are part of blockbuster drugs from a list of the top 50 drugs from worldwide sales of 2005.
- Enzyme function involves an active site that binds to the transition state for substrate (S) to product (P).
- Enzyme inhibition can be competitive, uncompetitive, non-competitive (allosteric), or irreversible (suicide).
- Proteases (proteinases, peptidases) hydrolytically cleave peptide amide bonds. They have four mechanistic classes: serine, cysteine, aspartic, and zinc.
- Protease specificity is determined by the binding of substrate amino acid side-chains near the cleavage site. Specific pocket nomenclature is used.
- Serine proteases like thrombin, tryptase, beta-lactamase, elastase, chymotrypsin, and HCV-NS3 have a catalytic triad that boosts serine nucleophilicity.
- Receptors are membrane-bound proteins that bind endogenous ligands (usually extracellular) to induce a physiological effect (usually intracellular).
- G-protein coupled, seven transmembrane spanning receptors are major types of receptors.
- α-adrenoceptors are a type of receptor.
- Binding to Receptors: Agonists bind and induce a signal. Antagonists bind and block signals.
- Ligands can be proteins, peptides, or small molecules.
- Agonists and antagonists bind competitively. Endogenous agonists often bind weakly, while successful antagonists bind tightly.
- Ion channels regulate passive ion flow across membranes dependent on electrical or concentration gradients, and some involve ion channels like hERG (iKr).
- Ion channels can be voltage-gated or ligand-gated. Ligands for ion channels can be other ions, small molecules, or toxins and venoms.
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Description
This lecture focuses on target classes in advanced medicinal chemistry and the drug discovery process. It details stages from target identification to candidate drug development, highlighting key biological mechanisms. Learn about major blockbuster drugs and their mechanisms of action.
