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PHAR300 > L22 Drug Design 1: Basic research > Flashcards

L22 Drug Design 1: Basic research Flashcards

1
Q

What questions need to be answered before drug approval by reputable government agency

A

Does the drug work
What are the side effects
How does it compare to what’s already available

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2
Q

What do risk-benefit analysis’ assess

A

do benefits outweigh the side effects? how do these risks and benefits compare to drugs already on the market

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3
Q

What are the current major killers?

A

cancer and heart disease

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4
Q

What are some drug designs for the future?

A

antibodies, cytokines, cells, etc.
personalized therapy

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5
Q

What is pathological research

A

research basic problems, abnormalities behind disease

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6
Q

What is pharmacological research

A

how certain drugs and potential drugs can modify the course of a disease

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7
Q

TF: Drug companies spend the second most money on research, following computer software and services companies

A

False, drug companies spend the most $$$

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8
Q

Why is it getting more expensive to research new drugs?

A

all the easy ones have already been researched

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9
Q

What is the current Toal cost of drug development and testing per year?

A

> 90 billion dollars

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10
Q

Why is Alzheimer’s disease so difficult to develop a drug for?

A

the basic pathophysiology/pathogenesis is unknown

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11
Q

What characterizes AD?

A

deposition of amyloid plaques in the brain which are associated with destruction of the brain

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12
Q

What’s Eli Lilly?

A

Flop company that developed a drug for AD ultimately proven to be useless compared to placebo during longer periods of testing
lost 1 billion dollars ouch

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13
Q

What is Aducanumab

A

a monoclonal antibody (MAB) that removes amyloid fibre via immune system before the amyloid plaques are even made (for AD)

minimal efficacy, expensive injections required for the rest of ones life

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14
Q

What are some reasons for drugs to be rejected in clinical testing?

A

-toxicity in animals
-high costs
-lack of efficacy
-pharmacokinetics
-side effects

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15
Q

Why are there less antibiotics being developed despite the arising antibiotic resistance problem?

A

they are not profitable

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16
Q

How much do clinical trials usually cost? How much time does it take?

A

$4 billion
10 years

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17
Q

Which drugs make the most profit (3)

A
  1. inflammatory conditions
  2. diabetes
  3. cancer
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18
Q

What are currently major selling drugs?

A

MAB for cancer
CV problems
skin problems (e.g. psoriasis)

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19
Q

What is preclinical research

A

it is the first phase of drug development (following the ‘idea’)
basic pharmacology and toxicology are looked into to see if the drug works, if it has any side effects/risks

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20
Q

What are current major challenges in healthcare?

A

-chronic diseases (e.g. AD, PD, arthritis)
-cancer
-CDV (MI, stroke)
-emerging infections and pollution

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21
Q

TF: government does most of the clinical research while industries (PhRMA member companies) focus on basic research

A

False, government funds bail research and some of the initial translation research in animals while industries do almost all clinical research (testing in humans)

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22
Q

Understanding og _ is at the core of drug development

A

pathogenesis

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23
Q

TF: drugs can be studied on individual cells

A

True

cell extracts can be used to study the mechanism of action of new drugs

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24
Q

Why is drug target identification considered the goal? What are examples of drug targets? What are the current most common drug targets?

A

Knowing the target allows for drug development

targets can be ligand-gated ion channels, GPCRs, enzymes, receptors, etc.

current drug targets are enzymes and receptors

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25
Q

What does the drug that treats HIV target?

A

HIV protease (enzyme) inhibitor

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26
Q

What are possible causes for side-effects

A

multiple control pathways present in the human body, drug target may be present in multiple tissues, disease may have multiple targets that must be acted on

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27
Q

Why are pharmacogenomics important for drug development

A

We try to select people who will respond to particular drug based on their genetics to avoid terrible side effects (some people may be more vulnerable)

genetic polymorhpisms related to pharmacokinetics and pharmacodynamics lets us know who shouldn’t be administered the drug

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28
Q

What causes cystic fibrosis

A

individuals are unable to make a particular chloride channel causing mucus buildup in lungs

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29
Q

How is cystic fibrosis treated

A

gene therapy

viral vector carrying new gene into cell inserts this gene into the nucleus of the cell. Cell can now encode the missing protein

30
Q

What is a recent and successful example of gene therapy?

A

replacement of sickle-cell/thalassemia genes with normal RBC gene using CRISPR

31
Q

TF: CRISPR is used for gene therapy

A

True

32
Q

What happens during sickle cell disease

A

RBC are abnormally shaped resulting in them transporting fewer hemoglobins and thus less oxygen

33
Q

What is pregenomics

A

disease description, uniform disease, patient homogeneity, universal
therapeutic strategy

34
Q

What is genomics

A

disease mechanism, disease heterogeneity, individual variation, patient risk profiling, pharmacogenomics, and targeted care

35
Q

TF: Environmental changes can cause changes in gene expression

A

True

36
Q

What is microarray technology

A

DNA complementary to genes of interest is generated and laid out in microscopic quantities on solid surfaces at defined positions

DNA from samples is eluted over surface-complementary DNA binds

Presence of bound DNA is detected by fluorescence following laser excitation

37
Q

what is angiogenesis

A

the growth of new blood vessels (around a tumour)

38
Q

How do you go about finding what ligands bind to your target?

A

Combinatorial chemistry gives thousands of potential compounds that can be tested (compound library)

promising compounds are selected and further tested

39
Q

What are “lead compounds”

A

compounds that are used during pre-clinical testing that have been screened from a compound library

if one is deemed useful during pre-clinical testing, it is optimized (make thousands of variations) and then tested

40
Q

What is lead optimization

A

when a lead compound is used to make thousands of variations to find a compatible ligand

41
Q

What is high throughput screening

A

testing thousands of compounds made in combinatorial chemistry
takes less time than manual screening

42
Q

How many compounds can be screened per day when using robotics + bioinformatics

A

20 000 compounds per day

43
Q

What are some possible test systems used during drug development

A

mammalian cells, microbes, human hepatocytes, microsomes, synthetic membranes, beads, etc.

44
Q

TF: combinatorial chemistry is done in vivo

A

False, it is done in vitro

then you can move along to in vivo studies in animal models

45
Q

What are the requirements for high-throughput screening

A
  1. suitable compound libraries
  2. assay method configured for automation
  3. robotics work station
  4. computerized system capable of handling the data
46
Q

What are ways in which responses from ligand binding to target i.e. drug can be assessed

A

fluorescence, luminescence, enzymatic, radioactive, immunological

47
Q

What is ‘automated ligand identification system’

A

a way of identifying potential ligands: target is mixed with a bunch of potential ligands. solution is then washed to see which ligands had the highest affinity via mass spectrometry

48
Q

What animal has been used in a multitude of studies due to its nervous system and embryonic development

A

zebrafish

49
Q

HTS (high-throughput screening) cannot evaluate: (5)

A
  1. bioavailability
  2. pharmacokinetics
  3. toxicity
  4. mutagenicity
  5. specificity
50
Q

How are yeast cells used to assess mutagenicity of a compound

A

yeast cells have DNA repair genes that are expresses in response to mutagens that induce damage to DNA. coupling these DNA repair genes with luciferase and assessing fluorescence can help detect DNA damage

more fluorescence = more DNA damage = mutagen

51
Q

How would you test for chemotaxis and metastasis

A

chemotactic factor on one side of the filer and see if that draws the cells from the other side

this allows to see if a drug is capable of blocking metastasis

52
Q

Most new drugs are eliminated during which stage of drug development?

A

clinical development

53
Q

What is bioinformatics

A

using softwares to aid in drug development and understanding go biological data

54
Q

What is computational chemistry

A

branch of chemistry that uses computer simulations and theoretical methods to study and understand chemical systems. It involves the application of mathematical models and algorithms to simulate the behavior of molecules and analyze their properties.

55
Q

TF: Computational chemistry was used to develop the drug that cures AIDS (HIV protease inhibitor)

A

True

56
Q

What is Ibrutinib (Imbruvica)

A

a drug that blocks an enzyme that is over expressed in malignant B cells (chronic lymphocytic leukemia)

It was developed using computational chemistry

57
Q

what do PCSK9 inhibitors do? What are they used for

A

PCSK9 inhibitors are used to treat atherosclerosis. They are MABs

it blocks the PCSK9 enzyme that is involved in degrading LDL cholesterol receptors which are responsible for decreasing cholesterol in circulation

PCSK9 inhibitor thus increasing the number of LDL receptors recycled back to the membrane and increases cholesterol clearance

58
Q

The bridge between what 3 fields has increasing efficiency and speed of drug development

A

genomics, combinatorial chemistry, bioinformatics

59
Q

What is biosimulation

A

a way of simulating pathogenesis and mechanisms of biological pathways implicated in diseases

useful for drug discover and minimizing side effects

60
Q

How are monoclonal antibodies made

A

made from a combination of species (hybridomas): combination of mouse and human antibodies, variable regions derived from primates, or purely human antibodies

61
Q

What are some strategies to avoid formation of anti mouse antibodies (4)

A
  1. chimeric antibodies (mouse variable region, human constant region)
  2. privatized antibodies ( chimeric with primate derived variable region)
  3. humanized antibodies (all human except antigen recognition site)
  4. transgenic mouse antibodies (fully humanized antibodies)
62
Q

MABs have been used to treat…

A

rheumatoid arthritis, Crohn’s disease, cancers (B cell malignancies CLL, breast cancers), osteoporosis

63
Q

How are MABs used to treat osteoporosis

A

the antibodies target osteoclasts which are responsible for breaking down the bone

64
Q

How are MABs used to treat beast cancer

A

the antibodies target HER2 (human epidermal growth factor receptor 2)

65
Q

What are some targets for MABs when it comes to tumours?

A

the tumour itself, its microenvironment, its blood supply

66
Q

What is adalimumab used for

A

TNF (tumour necrosis factor) inhibition for treating autoimmune diseases like rheumatoid arthritis, psoriasis, Crohn’s disease

67
Q

why is TNF (tumour necrosis factor) a big target for treating autoimmune diseases

A

it is found in many tissues and is important in immune resoinses

68
Q

What is Infliximab used for?

A

rheumatoid arthritis

69
Q

TF: over 90% of animal models are rodents

A

True

70
Q

Which test can be used to look for mutants?

A

Ames test
DNA repair genes + luciferase test in yeast cells

71
Q

What are the 4 steps in the first phase of drug discovery?

A
  1. find target
  2. find a lead
  3. optimize lead
  4. ADMET (absorption, distribution, metabolism, excretion, toxicity)

you can then file an application for a clinical trial

72
Q

What is golden rice

A

rice infused with beta-carotene (vitamin A provitamin) that is isolated from beta-carotene gene in daffodils

to help fight against vitamin A deficiency

PHAR300 (13 decks)

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