Advanced Medicinal Chemistry Lecture 1

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Questions and Answers

What is the primary mechanism through which successful antagonists typically bind to their targets?

  • Enthalpy driven binding
  • Reversible binding
  • Entropy driven binding (correct)
  • Electrostatic binding

Which ion channel blockade is associated with prolongation of the cardiac Q-T interval?

  • Na+ channel blockade
  • hERG (iKr) channel blockade (correct)
  • Ca++ channel blockade
  • K+ channel blockade

What differentiates agonists from antagonists in pharmacological terms?

  • Agonists bind weakly while antagonists bind tightly
  • Agonists induce conformational changes while antagonists do not (correct)
  • Agonists block receptor activity while antagonists activate receptors
  • Agonists compete with all types of binding while antagonists do not

Which of the following statements is true about ion channels?

<p>Ion channels can be either voltage-gated or ligand-gated (B)</p> Signup and view all the answers

Which of the following drugs emerged from calcium-channel antagonist programs?

<p>Amlodipine (A)</p> Signup and view all the answers

What type of inhibition involves an inhibitor binding only to the enzyme-substrate (ES) complex?

<p>Uncompetitive inhibition (B)</p> Signup and view all the answers

Which inhibition type allows partially inhibited enzymes to still turn over substrate?

<p>Non-competitive inhibition (C)</p> Signup and view all the answers

Which of the following is a characteristic of irreversible inhibition?

<p>The inhibitor covalently modifies the enzyme. (C)</p> Signup and view all the answers

What is the main function of proteases?

<p>To hydrolytically cleave peptidic amide bonds (A)</p> Signup and view all the answers

Endopeptidases have cleavage sites that can be located where in the substrate?

<p>Anywhere in the substrate (A)</p> Signup and view all the answers

Which statement correctly describes the specificity of proteases?

<p>Protease specificity is determined by substrate amino acid side-chains near the cleavage site. (C)</p> Signup and view all the answers

Which of the following is an example of irreversible inhibition?

<p>Amoxicillin (D)</p> Signup and view all the answers

What is the primary role of allosteric inhibitors in non-competitive inhibition?

<p>To change the enzyme conformation and reduce activity (C)</p> 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?

<p>Aspartic proteases (C)</p> 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?

<p>Covalent modifications (C)</p> Signup and view all the answers

What is the role of the catalytic triad in serine proteases?

<p>It enhances serine nucleophilicity. (D)</p> Signup and view all the answers

Which of the following describes the action of agonists at receptors?

<p>They provoke a signal through conformational changes. (A)</p> Signup and view all the answers

What characterizes the majority of known receptors?

<p>They span the membrane seven times. (C)</p> Signup and view all the answers

Which type of ligand induces no signal when bound to a receptor?

<p>Antagonist (A)</p> Signup and view all the answers

What is the significance of the P1 site in serine proteases?

<p>It's the primary specificity site for substrates. (D)</p> Signup and view all the answers

What happens when an excited-state receptor is activated?

<p>It generates a physiological signal. (D)</p> Signup and view all the answers

What do inhibitors of serine proteases typically do?

<p>They mimic stable tetrahedral intermediates. (A)</p> Signup and view all the answers

In the context of GPCRs, what role do the intracellular loops play?

<p>They facilitate G-protein coupling. (D)</p> Signup and view all the answers

Which of the following is NOT a characteristic of receptors?

<p>They exclusively bind ligands within the cytoplasm. (C)</p> Signup and view all the answers

Which of the following is true about thrombin and chymotrypsin?

<p>They are examples of serine proteases. (D)</p> Signup and view all the answers

What is the primary purpose of High Throughput Screening (HTS) in the drug discovery process?

<p>To identify new drug candidates (D)</p> Signup and view all the answers

Which category of enzyme inhibitors works by altering the enzyme's active site directly?

<p>Competitive inhibitors (A)</p> Signup and view all the answers

What is a common characteristic of partial agonists?

<p>They activate the receptor but less effectively than full agonists (A)</p> Signup and view all the answers

In the drug discovery process, how long does the Hit-to-Lead (HtL) phase typically take?

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

What type of drug is Lipitor and what is its primary mechanism?

<p>HMG CoA inhibitor; it lowers cholesterol levels (B)</p> Signup and view all the answers

What does the 'Lead Optimization' phase in drug development focus on?

<p>Improving the pharmacological properties of lead compounds (A)</p> Signup and view all the answers

What type of inhibitors binds to sites other than the active site?

<p>Allosteric inhibitors (B)</p> Signup and view all the answers

Which class of biological mechanisms do ion channel blockers fall into?

<p>Effectors (B)</p> Signup and view all the answers

What is the main function of the active site in an enzyme?

<p>To bind substrates and inhibitors (D)</p> Signup and view all the answers

What characterizes inverse agonists in relation to receptor activity?

<p>They stabilize the inactive form of the receptor (A)</p> Signup and view all the answers

What is the significance of Free Energy in enzyme reactions?

<p>It reflects the energy required to form the transition state (A)</p> Signup and view all the answers

Which type of biological mechanism typically involves interaction between two proteins?

<p>Protein-Protein interactions (B)</p> Signup and view all the answers

What duration does candidate drug development typically take following lead optimization?

<p>1-2 years (A)</p> Signup and view all the answers

What does the acronym 'CD' refer to in the context of the drug discovery process?

<p>Candidate Drug (A)</p> Signup and view all the answers

Flashcards

Drug Discovery Process

The steps involved in identifying, optimizing, and developing a new drug.

Target Identification

The initial step in drug discovery, focusing on finding a biological target to modify.

High-Throughput Screening (HTS)

A method used in the drug discovery process to screen many molecules quickly for activity.

Active-to-Hit (AtH)

Conversion of promising molecules from HTS to active molecules interacting with the targeted receptor.

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Hit-to-Lead (HtL)

The stage in drug discovery when active molecules (hits) are further developed and refined into more powerful lead compounds.

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Lead Optimization (LO)

Refining and improving the lead compound's properties, like potency, safety, and pharmacokinetics (how it's absorbed, metabolized, distributed, and excreted).

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Candidate Drug (CD)

A drug that has passed pre-clinical testing and is ready to enter clinical trials.

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Biological Targets

Molecules or structures in living organisms that can be manipulated by drugs to treat diseases.

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Receptor Agonists

Substances that activate a biological receptor to initiate a response.

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Enzyme Inhibitors

Substances that slow down or stop the activity of an enzyme.

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Enzyme Inhibition Mechanism

Different ways in which molecules inhibit an enzyme:

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Active Site

The specific region on an enzyme where the substrate binds and the reaction takes place.

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Blockbuster Drugs

Drugs with very high worldwide sales.

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Lipitor

A cholesterol-lowering drug, HMG CoA inhibitor.

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Plavix

An anti-platelet drug.

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Competitive Inhibition

An inhibitor competes with the substrate for the enzyme's active site, thus reducing the enzyme-substrate complex formation, reducing the reaction rate.

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Uncompetitive Inhibition

Inhibitor binds only to the enzyme-substrate complex (ES), forming an inactive enzyme-substrate-inhibitor complex (EIS).

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Non-competitive Inhibition

Inhibitor binds to a site other than the active site, altering the enzyme's shape and thus reducing activity; the enzyme-substrate complex formation is not prevented.

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Irreversible Inhibition

Inhibitor binds covalently to the enzyme, permanently disabling it.

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Suicide Inhibitors

A type of irreversible inhibitor that resembles the substrate and is modified by the enzyme, thus trapping the enzyme.

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Proteases

Enzymes that catalyze the hydrolysis of peptide bonds in proteins.

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Endopeptidases

Proteases that cleave peptide bonds within the protein's interior.

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Exopeptidases

Proteases that cleave peptide bonds at the protein's termini (ends).

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Specificity Pocket

Regions of proteases containing amino acids, which interact with polypeptide chain components near a cleavage site.

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Serine Protease

A class of proteases that utilizes a catalytic serine residue.

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Agonist

A molecule that binds to a receptor and initiates a response.

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Antagonist

A molecule that blocks the action of an agonist by binding to the same receptor site, but without triggering a response.

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Inverse Agonist

A molecule that binds to a receptor and produces the opposite effect of an agonist.

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Membrane Potential

The difference in electrical charge across the cell membrane.

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Ion Channels

Proteins embedded in the cell membrane that allow specific ions to pass through.

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Catalytic Triad

A set of three amino acid residues (usually Asp, His, Ser) found in serine proteases that work together to facilitate catalysis.

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Inhibitors of Serine Proteases

Molecules that bind to serine proteases and prevent them from cleaving peptide bonds. They often mimic or create stable tetrahedral intermediates.

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Beta-Lactams

A class of antibiotics that inhibit bacterial enzymes. They are known for their ability to form stable tetrahedral intermediates with bacterial transpeptidases.

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Trifluoromethyl Ketones

A class of molecules that are potent inhibitors of serine proteases. They work by binding to the active site and mimicking the transition state of the reaction.

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Receptor

Membrane-bound proteins that bind to ligands and initiate a cellular response. They are often the first step in a signaling cascade.

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G-Protein Coupled Receptors (GPCRs)

A large family of receptors that are characterized by their seven transmembrane spanning domains. They interact with G proteins to mediate downstream signaling.

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Excited-State Receptor

The conformational state of a receptor after ligand binding. This state is responsible for initiating a signal.

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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.

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