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Drug Discovery (2037A) > Block 1 > Flashcards

Block 1 Flashcards

1
Q

What is drug repurposing?

A

Drug repurposing is the use of an existing and already approved drug for new things.

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2
Q

What is drug repositioning?

A

Drug repositioning is the development of an existing, previously evaluated but unapproved active pharmaceutical ingredient for the treatment of a different disease.

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3
Q

What is the FDA?

A

The FDA is the Food and Drug Administration and they are responsible for ensuring the efficacy and safety of drugs.

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4
Q

What are the stages of drug discovery and development?

A

D.I.L.P.C.F

  1. Disease identification.
  2. Identification of a therapeutic target.
  3. Lead identification (HTS and in vitro and in vivo pharmacology).
  4. Preclinical trials (HTS and animal testing).
  5. Clinical trials.
  6. FDA approval.
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5
Q

What is a bioassay?

A

A bioassay is any qualitative or quantitative analysis of a substance that uses a living system, such as an intact cell, as a component.

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6
Q

Primary bioassays are primarily:

A

Primary bioassays are primarily in vitro.

A 1% hit rate is considered reasonable.

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7
Q

Secondary bioassays are primarily:

A

Secondary bioassays are primarily in vivo.

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8
Q

What are HITS?

A

HITS are compounds that display the desired activity in a compound screen and whose activity is confirmed upon retesting.

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9
Q

What is HTS?

A

HTS is high-throughput screening.

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10
Q

What are the points to consider during assay development?

A
  1. The three R’s (Relevance, robustness, and reliability).
  2. Practicality.
  3. Feasibility.
  4. Automation.
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11
Q

Screening assays are made in?

A

Screening assays are made in microtiter plates.

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12
Q

What is a druggable target?

A

A druggable target is a protein, peptide, or nucleic acid with activity that can be modulated by a drug, consisting of a small molecular weight or a biologic, such as an antibody or a recombinant protein.

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13
Q

What do drugs target?

A

Drugs target enzymes, ion channels, transporters, and G-protein coupled receptors.

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14
Q

What are the functions of proteins?

A
  1. Act as catalysts (Catalysis).
  2. Transport substances within cells and from cell to cell.
  3. Transfer information.
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15
Q

What is the hierarchy of protein structure?

A
  1. Primary structure (amino acid sequence).
  2. Secondary structure (alpha-helix and beta-sheet).
  3. Tertiary structure (3D structure).
  4. Quaternary structure (interaction with other proteins)
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16
Q

What are enzymes?

A

Enzymes are protein catalysts that facilitate the transformations required to sustain life.

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17
Q

What are the 6 classifications of enzymes?

A

T.H.O.I.L.L

  1. Transferase.
  2. Hydrolase.
  3. Oxidoreductase.
  4. Isomerase.
  5. Lyase.
  6. Ligase
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18
Q

What is the function of Oxidoreductase?

A

Oxidoreductase catalyzes redox chemistry and transfers electrons between molecules.

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19
Q

What is the function of transferase?

A

Transferase catalyzes the transfer of a functional group from one compound to another.

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20
Q

What is the function of Hydrolase?

A

Hydrolase catalyzes the hydrolysis of a chemical bond.

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21
Q

What is the function of lyase?

A

Lyase catalyzes the cleavage of a chemical bond, forming a double bond or a ring.

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22
Q

What is the function of isomerase?

A

Isomerase catalyzes the formation of isomers.

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23
Q

What is the function of ligase?

A

Ligase catalyzes the joining of large molecules with a chemical bond.

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24
Q

What are the general functions of enzymes?

A
  1. Act as catalysts.
  2. Speeds up time for a reaction to reach equilibrium.
  3. Lowers the activation energy of a reaction.
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25
Q

What is the active site?

A

The active site is a hydrophobic cleft on the surface of an enzyme that accepts reactants.

The active site contains amino acids that bind reactants and catalyze the reaction.

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26
Q

What dictates enzyme specificity?

A

The active site dictates enzyme specificity.

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27
Q

What is the induced fit model of enzyme binding?

A

The induced-fit model states that the active site of the enzyme is nearly the right shape for the substrate, so the substrate alters the shape of the active site by binding to it.

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28
Q

How can the active site be blocked?

A

Molecules with strong binding interactions can block the active site as they will bind to the active site and then not leave.

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29
Q

What are the 3 types of enzyme inhibitors?

A

C.I.A

  1. Competitive inhibitors.
  2. Irreversible inhibitors.
  3. Allosteric inhibitors.
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30
Q

How do competitive inhibitors inhibit enzyme activity?

A

Competitive inhibitors inhibit enzyme activity by blocking the active site of an enzyme. (Is reversible as there is no covalent bonding, can be reversed by increasing the [ ] of the substrate.

Eg. Tamiflu

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31
Q

How do irreversible inhibitors inhibit enzyme activity?

A

Irreversible inhibitors inhibit enzyme activity by covalently attaching to the active site, thus blocking substrate entry and inactivating the enzyme.

Eg. Penicillin G

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32
Q

How do allosteric inhibitors inhibit enzyme activity?

A

Allosteric inhibitors inhibit enzyme activity by influencing sites other than the active site of the enzyme. This induces conformational changes to the shape of the active site to such a degree that the substrate is unable to get to it even though it is unoccupied.

Eg. MEK inhibitor.

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33
Q

Which types of enzyme inhibitors do pharmaceutical companies favor and why?

A

Pharmaceutical companies favor competitive and allosteric inhibitors.

Irreversible inhibitors are frowned upon as if they accidentally inhibit the wrong thing due to a similar biding site then the effects cannot be undone.

Irreversible inhibitors can also negatively alter the rate at which drugs are cleared from the body.

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34
Q

What are GPCR’s?

A

GPCR’s are G-protein-coupled receptors.

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35
Q

What is the function of receptors?

A

Receptors enable cell to cell communication by allowing the flow of information across the plasma membrane.

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36
Q

What are neurotransmitters?

A

Neurotransmitters are chemical messengers released from nerve endings, that travel across synapses and to receptors on target cells.

Usually short lived and responsible for messages between individual cells.

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37
Q

What are Hormones?

A

Hormones are chemical messengers that are released from cells or glands and travel some distance to bind with receptors on target cells throughout the body.

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38
Q

What are G-proteins?

A

G-proteins (guanine nucleotide-binding proteins) are a family of proteins that act as molecular switches inside cells.

They transmit signals from outside stimuli into the interior of the cell.

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39
Q

What turns G-proteins on and off?

A

Guanosine triphosphate (GTP) turns G-proteins on.

Guanosine diphosphate (GDP) turns G-proteins off.

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40
Q

What are the 5 families of GPCR’s?

A
  1. Rhodopsin.
  2. Secretin.
  3. Frizzled GPCRs.
  4. Glutamate receptors.
  5. Adhesion class of GPCRs.
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41
Q

What is the function of the Rhodopsin family of GPCRs?

A

Rhodopsin = Function in the CNS, cardiovascular regulation, and pain perception.

Serotonin, dopamine, angiotensin 2, prostaglandin receptors.

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42
Q

What is the function of the Secretin family of GPCRs?

A

Secretin = Parathyroid hormone and glucagon receptors.

43
Q

What is the function of the Frizzled GPCRs family?

A

Frizzed GPCRs = Cell differentiation and proliferation through the Wnt signaling pathway.

44
Q

What is the function of the Glutamate receptor family of GPCRs?

A

Glutamate receptor = Modulation of excitability of synaptic cells, and nerve transmission.

45
Q

What is the function of the Adhesion class of GPCRs?

A

Adhesion class of GPCRs = Cell adhesion and cellular response.

46
Q

What are secondary messengers and what are the two types of secondary messengers?

A

Secondary messengers are molecules that transmit signals from GPCRs to the cellular machinery.

2 types of secondary messenger systems:

  1. cAMP (cyclic adenosine monophosphate) system.
  2. Phosphatidylinositol system.
47
Q

What are the 2 classes of drugs that can target GPCRs?

A

Agonists and antagonists.

48
Q

How do agonists target GPCRs?

A

Agonists mimic the natural substrate to produce a cellular response.

Binds reversibly to the binding site.
Induced fit.
Activates receptor.
Often similar in structure to the natural messenger.

49
Q

How do antagonists target GPCRs?

A

Antagonists target GPCRs by binding to the GPCR but not eliciting a cellular response.

Binds reversibly.
Differing induced fit to not activate the receptor.
No reaction takes place.
Blocks messenger from the binding site.

50
Q

How do inverse agonists function?

A

Inverse agonists block the ligand, but produce a cellular response opposite to the natural ligand.

51
Q

What are the efficacies of agonists, antagonists, and inverse agonists?

A

Agonists: Positive efficacy.

Inverse agonists: Negative efficacy.

Antagonists: Zero efficacy.

52
Q

What are ion channels?

A

ion channels are transmembrane proteins that regulate the flow of ions across biological barriers.

53
Q

What is membrane potential?

A

Membrane potential refers to electrical gradients across cellular barriers resulting from differences in ion [ ]’s on the inside and outside of cells created by the selective movement of ions across the cellular barrier.

54
Q

What is hyperpolarization?

A

Hyperpolarization refers to when the membrane potential becomes more negative at a particular spot on the neuron’s membrane.

55
Q

Voltage-gated channels cannot be modulated by agonists and antagonists, so how can they be modulated?

A

Voltage-gated channels can be modulated by blocking the channel directly or by allosteric modulation.

Diazoxide is an ion channel opener.

Amiodarone is an ion channel closer.

56
Q

What are MTPs?

A

MTPs are membrane transport proteins that transport small molecules down a concentration gradient via diffusion.

Their modulation is a major tool in the treatment of psychiatric disorders.

57
Q

How do MTPs work?

A

Membrane transport protein function:

Solute binds to MTP and induces conformational changes that transfer the solute molecule from one side of the membrane to the other.

58
Q

What are the three types of MTPs?

A
  1. Uniport ———–>
  2. Symport ————>
    - ———–>
  3. Antiport ————>
59
Q

Discuss the 3 types of transport inhibition.

A
  1. Occupy the substrate-binding site with a substrate mimic that is not transported through the membrane. (Blocking the pipe.)
  2. Use a substrate mimic that is preferentially transported instead of the normal substrate.
  3. Induce conformational changes via allosteric regulation.
60
Q

How does cocaine addiction occur?

A
  1. Dopamine transporters are blocked, thereby preventing the reuptake of dopamine.
  2. Rapid increase in extracellular dopamine levels.
  3. Chronis cocaine use leads to the upregulating of dopamine transporters, therefore you need more cocaine to get the same high.
61
Q

What is the therapeutic index (T.I)?

A

The therapeutic index is a measure of drug safety, calculated by the ratio of the drug dose that produces toxicity to the dose that produces a clinically desired response.

T.I =TD50 / ED50 (Higher the T.I the safer the drug)

The dose that produces toxic effects in 50% of the population is divided by the dose that produces a therapeutic effect in 50% of the population.

ED50 must not be higher than TD50 for obvious reasons.

62
Q

What are the three types of cultures?

A

Organ cultures, cell cultures, and tissue cultures.

63
Q

What are the advantages of using cultures?

A
  1. Absolute control over the environment.
  2. Homogeneity of the sample.
  3. Less compound needed than in animal models.
64
Q

What are the disadvantages of cultures?

A
  1. Hard to maintain.
  2. Expensive.
  3. Instability.
  4. Loss of specialized function (dedifferentiation).
65
Q

What is a cell culture?

A

Cell culture: The growing of cells under controlled conditions.

Pros:

  1. Development of cell lines over several generations.
  2. Scale-up is possible.

Cons:

  1. Cells may loose some differentiated charachteristics.
66
Q

What is a primary cell culture?

A

Primary cell culture refers to cells derived directly from animal tissue.

Primary cultures:

  1. Stay differentiated (specialized).
  2. Exhibit contact inhibition (a growth mechanism that functions to keep cells growing into a monolayer (1 cell thick layer)).
67
Q

What is contact inhibition?

A

Contact inhibition is a growth mechanism that functions to keep cells growing into a monolayer (1 cell thick layer).

68
Q

What is a secondary cell culture?

A

Secondary cell culture refers to cells derived from a primary culture.

Secondary cell cultures:

  1. Maintain differentiation.
  2. Exhibit contact inhibition.
  3. Cell population is becoming more homogenous.
69
Q

What is organ culture and what are the pros and cons of organ culture?

A

Organ Culture: The entire embryos or organs are excised
from the body and culture.

Pros:

  1. Normal physiological functions are maintained
  2. Cells remain fully differentiated.

Cons:

  1. Scale-up is not recommended.
  2. Difficult to maintain.
  3. Fresh explanation is required for every experiment.
70
Q

What is tissue culture and what are the pros and cons of tissue culture?

A

Tissue culture: Fragments of excised tissue are grown in culture media.

Pros:

  1. Some normal functions may be maintained.
  2. Better than organ culture for scale-up but not ideal.

Cons.

  1. Original organization of tissue is lost.
71
Q

What are cell cultures used for?

A
  1. Model systems for studying basic cell biology, interactions between disease-causing agents and cells, effects of drugs on cells, process and triggering of aging & nutritional studies.
  2. Toxicity testing, studying the effects of new drugs.
  3. Cancer research: Study the function of various chemicals, virus & radiation to convert normal cultured cells to cancerous cells.
72
Q

What is morphology?

A

Shape and appearance of cells.

73
Q

What are the three types of cell morphology?

A
  1. Epithelial (Flat and sort of round).
  2. Lymphoblast (Round).
  3. Fibroblast (tube-like).
74
Q

What is meant by the term anchorage dependent?

A

Anchorage dependent: Cells derived from normal tissues that only grow on a suitable substrate. Eg. Tissue cells.

75
Q

What is meant by the term anchorage independent?

A

Anchorage-independent: Suspension cells. Eg, Blood cells.

76
Q

Why do we passage cells?

A

We passage cells to maintain them and prevent them from overgrowing, as well as to increase the cell number for experiments and storage.

77
Q

Why do we subculture cells?

A

We subculture cells as once the cells have covered the substrate, growth slows and ceases, therefore we subculture them to keep them growing.

(Enzymes like trypsin are used to detach the cells from the surface).

78
Q

What is confluency?

A

Confluency is the % of the screen that is covered by cells.

79
Q

What do cells need to grow?

A
  1. A substrate.
  2. Nutrients.
  3. Humidity, 37 degree C temp, CO2.
80
Q

Why must cell cultivation be done in a sterile environment?

A

Cell cultivation must be done in a sterile environment to prevent contamination.

81
Q

What are the two types of cell culture contamination?

A

Chemical (tricky to detect) and biological (easy to detect) contamination.

82
Q

Discuss the MTT assay:

A

The MTT assay tests cell viability. The higher the absorbance of formazan, the higher the no. of viable cells. Change from yellow to purple if absorbed).

83
Q

Why does the FDA require animal testing when so much can be done in vitro?

A

In vitro is only an incomplete model of a far more complicated system. In
whole animals, the net biological impact of a compound is the sum total of
the compound’s effect on all of the macromolecules, tissues, and organs
that it comes into contact with.

84
Q

Define Pharmacokinetics:

A

Pharmacokinetics: What happens to a compound when it enters a body.

85
Q

Define Pharmacodynamics:

A

Pharmacodynamics: What the compound does to the body.

86
Q

Discuss efficacy vs potency:

A

Efficacy is the capacity of a compound to produce a desired biological effect whilst potency is the amount of compound required to produce an effect of a given intensity.

87
Q

What is the therapeutic window?

A

The therapeutic window refers to the drug dose that will illicit a positive response while minimizing the negative effects.

88
Q

How can illness in animal models be induced?

A

Illness in animal models can be induced either through physical or chemical means.

89
Q

What are the three categories of animal models

A
  1. Homologous (Same causes, symptoms, and treatments as humans)(most desirable type of animal model).
  2. Isomorphic (Same symptoms and treatment as humans but different cause).
  3. Predictive (Minimal overlap but still some useful markers that can be used as a predictive tool).
90
Q

Discuss the limitations of using primates for animal testing.

A

Very few non-human primates are available for study,

  • are both difficult and expensive to maintain.
  • Their large size impacts compound supply issues, as potential therapeutics are most often dosed on a milligram per kilogram basis.
  • Larger animals require larger amounts of compounds, further driving up the expense of non-human primate studies.
  • Additional ethical considerations also come into play.
  • Non-human primates are typically used only when no other option is available.
91
Q

What is a Xenograft animal model?

A

The immunocompromised animal is given cancer cells either from patients or from standardized cell lines. The efficacy of treatments is then analyzed in the animal model as a prediction of efficacy in human treatment.

92
Q

What is an Alograft animal model?

A

An Allograft animal model is the same as a Xenograft animal model except it has mouse cancer cells instead of human cancer cells.

93
Q

What is a Structure-Activity Relationship (SAR)?

A

Structure-Activity Relationship (SAR):

The biological effect can change if the chemical structure changes.

94
Q

What is a Structure-Property Relationship (SPR)?

A

Structure-Property Relationship:

Physiochemical properties can change if the chemical structure changes.

95
Q

How is potency influenced by the electronic nature of the R group?

A

Electron donating R groups decrease potency (CH3, OCH3).

Electron withdrawing R groups increase potency (Cl, Br).

Therefore, new compounds should contain aromatic rings with electron-withdrawing R groups.

NB: Compounds, where the R group is an aromatic ring, will always be less potent than those with smaller substituents.

96
Q

Define the pharmacophore:

A

The pharmacophore is an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biologic target and to trigger (or block) its biologic response.

97
Q

Define the auxophore:

A

The remainder of the compound, parts of which may provide structural support for the position of the functionality within the pharmacophore but play no direct role in binding events.

98
Q

What is apopotosis?

A

Apoptosis or programmed cell death is the carefully coordinated collapse of the cell, protein degradation, and DNA fragmentation followed by the rapid engulfment of the corpses by neighboring cells.

99
Q

Why does apoptosis occur?

A

Apoptosis is needed for proper development (ie. resorption of the tadpole tail).

Apoptosis is needed to destroy cells that could be harmful (ie. cells infected with viruses).

100
Q

Discuss the differences between apoptosis and necrosis:

A

Apoptosis:

  • Cellular condensation.
  • Membranes remain intact.
  • Requires ATP.
  • Cell is phagocytosed, no tissue reaction.
  • Ladder-like DNA fragmentation.
  • In vivo, individual cells appear affected

Necrosis:

  • Cellular swelling.
  • Membranes are broken.
  • ATP is depleted.
  • Cell lyses, eliciting an inflammatory reaction.
  • DNA fragmentation is random or smeared.
  • In vivo, whole areas of the tissue are affected.
101
Q

Discuss the morphological events of apoptosis:

A

Morphological events of apoptosis:

  1. Cell shrinkage.
  2. Organelle reduction.
  3. Mitochondrial leakage.
  4. Chromatin condensation.
  5. Nuclear fragmentation.
  6. Membrane blebbing and changes.
102
Q

What is blebbing?

A

The control retained over the cell membrane & cytoskeleton allows intact pieces of the cell to separate for recognition & phagocytosis by macrophages.

(Pieces of cell eaten by macrophages)

103
Q

Discuss the 2 apoptotic pathways:

A

Intrinsic pathway:

DNA Damage –> Mitochondria or Cytochrome C –> Initiator Caspase 9 –> Effector Caspase 3 –> Programmed cell death.

Extrinsic pathway:

Death ligands –> Death receptors –> Initiator caspase 8 –> Effector caspase 3 –> Programmed cell death.

Drug Discovery (2037A) (4 decks)

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