Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Bench to bedside and beyond > 11. Drug discovery > Flashcards

11. Drug discovery Flashcards

1
Q

what happens to most drugs in development?

A

they fail and never make it to being treatments

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what is a hit?

A

A compound with confirmed activity against the desired target

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what is a lead?

A

An active compound with drug-like and some favourable pharmacological properties

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is a candidate?

A

an optimised lead ready for clinical development

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is pharmacokinetics?

A

how the body interacts with administered substances for the entire duration of exposure
- the effect of host on the drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is pharmacodynamics?

A

molecular, biochemical and physiological effects or actions of the drug
- the effect of the drug on the host

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Overview of drug discovery process

A
  1. a large number of molecules need to be explored to find 1 drug
  2. most time is spent in the discovery phase
  3. can take decades
  4. a lot of risk and investment is needed for clinical phase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

why do drugs fail in clinical trials?

A
  1. lack of efficacy in the patient. It is when the drug just doesn’t work well. Accounts for 40-50% of failure
  2. Unmanageable toxicity and side effects. Accounts for 30% of failure
  3. Poor drug-like reasons like it being metabolised too fast. accounts for 10-15% of failure
  4. Economic reasons. Just costs too much. accounts for 10% of failure
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what is phenotypic based drug discovery?

A
  1. disease model
  2. phenotypic assay
  3. lead identification - will it kill the bacteria?, don’t always need to know how it works?
  4. target identification
  5. lead optimisation
  6. preclinical trials
  7. Clinical trials
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what is target-based drug discovery?

A
  1. know the drug target
  2. target based assay to find a phenotypic effect
  3. lead identification
  4. lead optimisation
  5. preclinical trials
  6. clinical trials
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what makes a good drug target?

A
  1. disease modifying
  2. druggable
  3. assayable
  4. differentially expressed
  5. low liability to resistance
  6. vulnerable
  7. favourable intellectual property situation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what is meant by disease modifying?

A

doing something to effect the progression or outcome of the disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what is meant by druggable?

A

its activity can be modulated by a drug so normally small molecules or proteins not multicomplex proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is meant by assayable?

A

can use in high through put screening to screening 1000s of molecules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is meant by differentially expressed?

A

different in the normal state vs the diseased state

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what is meant by low liability to resistance?

A

low mutation rate

17
Q

what is meant by vulnerable?

A

the drug target is not in a body compartment that is hard to get too

18
Q

what is meant by a favourable intellectual property situation?

A

the idea is profitable and patentable for the person/company

19
Q

what are the Lipinski Rules?

A

a framework that looked at successful drugs and what they had in common
1. drugs are small <500Da
2. hydrophobicity is LogP<5
3. less than 5 hydrogen bond donors and less than 10 hydrogen bond acceptors
4. must be structurally rigid
5. polar surface area should be <140Å

20
Q

what off-target activity might a molecule do?

A
  1. hERG K+ channel binding which can indicate adverse cardiac effects
  2. Other can indicate neurotoxicity or addictiveness
  3. screen for activity against CNS receptors using biochemical assays
21
Q

What are specific drugs screened against to prevent side effects?

A
  1. molecules similar to the drug target
  2. other molecules interacting with the drug target
  3. other molecules in the vicinity
22
Q

what is ADME-(Tox)?

A

absorption distribution metabolism excretion (toxicology)

23
Q

what does ADME(Tox) look for?

A
  1. how readily the drug is absorbed
  2. how readily the drug is distributed
  3. is it likely to be readily excreted/too quickly to be effective?
  4. is it readily filtered out by the kidneys?
24
Q

why are animal models used?

A
  1. to evaluate safety and toxicity not to treat the condition
  2. how the drug is absorbed/distributed/excreted
  3. neutropenic mice are used to replicate immunocompromised state for opportunistic infections
25
Q

why is it important to have an appropriate animal model?

A

to be close enough to the human condition

26
Q

what is the process of preclinical development?

A

an iterative process of cycling characterising hits and making optimisations to reduce off target effects

27
Q

what is translational development ?

A
  1. the valley of death
  2. due to funding constraints research goes to die
  3. industry doesn’t want to spend the money. academia also doesn’t want to do it as it is generally out of their purview
  4. most experiments are boring and people do not want to do it
28
Q

What is a killer experiment?

A

definitive experiments that will put your hypothesis to a solid test.
It will either show you are right or kill your research and stop it going any further

29
Q

when do killer experiment happen?

A

in industry:
- do them early to see if the idea is viable and not waste money
in academia:
- do them later as there is still a chance to publish if you have enough research first

30
Q

what are phase 1 trials?

A
  1. initial knowledge of candidate in humans
  2. small numbers of healthy volunteers, often less than 10
  3. Checking tolerance and safety
  4. the pharmacokinetics and pharmacodynamics in humans
  5. optimise dosage and administration
  6. also look for food/drug interactions, special population, different formulations
  7. not looking for efficacy for the target condition
31
Q

Criteria to enter a phase 1 trial

A
  1. Regulatory approval
  2. studies supported by good laboratory practise
  3. pharmacologically relevant animal models
  4. supporting data from human derived models
  5. Toxicology
  6. quality/reproducibility of material
  7. design regimen
32
Q

what are phase 2 trials?

A
  1. patient with the target condition
  2. low 100s of patients
  3. based on phase 1 data for dosage and administration
  4. safety
33
Q

what are phase 3 trials?

A
  1. patients with the target condition
  2. usually around 300-3000 patients
  3. efficacy
  4. adverse reactions
  5. looking to see if the treatment is at least as good as existing treatment
  6. rare and long term side effects
  7. justify new drug application and regulatory approval
  8. needs to reflect patient diversity
34
Q

how can data science help drug discovery?

A
  1. prediction of chemical/pharmacological properties
  2. target biology and lead discovery
  3. machine learning or AI-driven discovery pipelines
35
Q

what are PAINS?

A
  1. pan-assay interference compounds
  2. molecule that produces lots of hits on assays but are not a good drug as lots of off target binding
36
Q

how can we predict ADME properties?

A

using chemical properties.
they could suggest if a drug can pass the blood brain barrier or be absorbed in the gut

37
Q

how could AI be used in drug development?

A

to predict which drug will work or work the best

Bench to bedside and beyond (20 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions