Drug Discovery and Development One Flashcards Preview

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Flashcards in Drug Discovery and Development One Deck (29):
1

Whats a general overview of the drug development pathway?

- Early stage research and discovery
- Preclinical studies
- Phase 1-3 clinical studies
- FDA review and approval

2

What does early stage research and discovery encompass?

- Target ID
- HIT discovery
- Lead Generation

3

What does target ID involve?

- Phenotypic screen
- HIT discovery
- Target ID

4

What are two types of screening for drug discovery?

- Target Based (knowledge of drug, choose targets to test)
- Phenotypic (test lots of receptors for effect)

5

Whats the advantages for target based screening of drugs?

Advantages:
- Application of molecular and chemical knowledge
- Small molecule screening strategy
- Biological development (i.e antibodies)

6

Whats the disadvantages for target based screening of drugs?

Disadvantages:
- Target might not be relevant to disease
- No therapeutic index

7

Whats the advantages of phenotypic based screening?

- Does not require knowledge of MOA
- More effective translation from assay to therapeutic impact

8

What are the disadvantages of phenotypic based screening?

- Optimizing properties with MOA knowledge
- Lower throughput than target based

9

In target based screening, what are some targets used?

- Ligand binding site
- Catalytic site (enzymes)
- Allosteric site
- Protein-protein interface
- Protein-membrane interactions

10

In target based screening how do we develop drugs?

- Makes molecules related to the known ligands (analogues)

or

- Screen for knew molecules based on the receptors and known ligand properties

11

In classical pharmacology, how are receptors classified?

Receptors were classified based on their ligand response profile

(classification could lead directly to new therapies)

12

Are ligands only recognized by one protein?

Different proteins can recognize the same ligand

13

Whats an example were drugs were developed based on being analogues to the known ligand?

- Adrenalin acts on adrenoreceptors
- Use antagonism for angina
- Use agonism for asthma

14

How is angina treated?

Use of propanalol as an antagonist at the b-receptor to decrease its heart rate, thus decreasing the work its performing/oxygen needs

- Doesnt affect contractile state

15

How are disease states used to develop drugs?

Critical evaluation of disease data generates a hypothesis about what is needed from a drug

16

What is a HIT discovery?

When the target phenotype is affected by a compound

17

During the development of propanolol, what pathway of analogues was unsuccessful?

Symmetrical analgoues

18

What is lead development?

Using a compound that is known to have the same affect (agonist, antagonist etc) as you want, and then looking into analogue structures (produce precise effect)

19

What was the inertial treatment for asthma?.

Adrenalin

20

Why was Adrenalin no longer used to treat asthma?

Caused hypertension, tachycardia etc as acted on all receptors

21

What was the current treatments for asthma based off?

Adrenalin analogues

22

What must be done in analogue envelopment?

- Toxicity and metabolic profiles must be developed

23

What is currently used to treat asthma?

Sulbutamol

24

Why is sulbutamol used?

B2 AR selective
Fast Onset
Longer acting than isoprenaline
Weaker binding
Best results by inhalation

25

Do different agonists stabilize different conformations of the activated receptor-binding pocket?

Protein bind to the ligand i.e protein changes shape not the ligand

26

Are chemical properties useful in discovery?

Yes, but must refine exactly what you are looking for

27

How can screening assays be clouded?

Interference of compounds inc:
- Optical interference
- Reactions
- Aggregates
- Pan Assay Interference Compounds (PAIN)

28

How can you prevent screening assays from being clouded?

- Known problem compounds can be filtered out based on substrucure

29

When you develop a library of known drug information, whats important about someone using it?

It will be context dependent

i.e Might say a drug doesnt work (but drug was tested under oral admin, when IV it works)