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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

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2
Q

what is a hit?

A

A compound with confirmed activity against the desired target

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3
Q

what is a lead?

A

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

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4
Q

what is a candidate?

A

an optimised lead ready for clinical development

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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

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6
Q

what is pharmacodynamics?

A

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

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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
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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
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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
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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
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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
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12
Q

what is meant by disease modifying?

A

doing something to effect the progression or outcome of the disease

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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

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14
Q

what is meant by assayable?

A

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

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15
Q

what is meant by differentially expressed?

A

different in the normal state vs the diseased state

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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
why is it important to have an appropriate animal model?
to be close enough to the human condition
26
what is the process of preclinical development?
an iterative process of cycling characterising hits and making optimisations to reduce off target effects
27
what is translational development ?
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
What is a killer experiment?
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
when do killer experiment happen?
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
what are phase 1 trials?
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
Criteria to enter a phase 1 trial
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
what are phase 2 trials?
1. patient with the target condition 2. low 100s of patients 3. based on phase 1 data for dosage and administration 4. safety
33
what are phase 3 trials?
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
how can data science help drug discovery?
1. prediction of chemical/pharmacological properties 2. target biology and lead discovery 3. machine learning or AI-driven discovery pipelines
35
what are PAINS?
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
how can we predict ADME properties?
using chemical properties. they could suggest if a drug can pass the blood brain barrier or be absorbed in the gut
37
how could AI be used in drug development?
to predict which drug will work or work the best

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