Drug Discovery and Development One

Question 1

Whats a general overview of the drug development pathway?

Answer 1

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

Question 2

What does early stage research and discovery encompass?

Answer 2

• Target ID
• HIT discovery
• Lead Generation

Question 3

What does target ID involve?

Answer 3

• Phenotypic screen
• HIT discovery
• Target ID

Question 4

What are two types of screening for drug discovery?

Answer 4

• Target Based (knowledge of drug, choose targets to test)

- Phenotypic (test lots of receptors for effect)

Question 5

Whats the advantages for target based screening of drugs?

Answer 5

Advantages:

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

Question 6

Whats the disadvantages for target based screening of drugs?

Answer 6

Disadvantages:

• Target might not be relevant to disease
• No therapeutic index

Question 7

Whats the advantages of phenotypic based screening?

Answer 7

• Does not require knowledge of MOA

- More effective translation from assay to therapeutic impact

Question 8

What are the disadvantages of phenotypic based screening?

Answer 8

• Optimizing properties with MOA knowledge

- Lower throughput than target based

Question 9

In target based screening, what are some targets used?

Answer 9

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

Question 10

In target based screening how do we develop drugs?

Answer 10

• Makes molecules related to the known ligands (analogues)

or

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

Question 11

In classical pharmacology, how are receptors classified?

Answer 11

Receptors were classified based on their ligand response profile

(classification could lead directly to new therapies)

Question 12

Are ligands only recognized by one protein?

Answer 12

Different proteins can recognize the same ligand

Question 13

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

Answer 13

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

Question 14

How is angina treated?

Answer 14

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

Question 15

How are disease states used to develop drugs?

Answer 15

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

Question 16

What is a HIT discovery?

Answer 16

When the target phenotype is affected by a compound

Question 17

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

Answer 17

Symmetrical analgoues

Question 18

What is lead development?

Answer 18

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)

Question 19

What was the inertial treatment for asthma?.

Answer 19

Adrenalin

Question 20

Why was Adrenalin no longer used to treat asthma?

Answer 20

Caused hypertension, tachycardia etc as acted on all receptors

Question 21

What was the current treatments for asthma based off?

Answer 21

Adrenalin analogues

Question 22

What must be done in analogue envelopment?

Answer 22

• Toxicity and metabolic profiles must be developed

Question 23

What is currently used to treat asthma?

Answer 23

Sulbutamol

Question 24

Why is sulbutamol used?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

Are chemical properties useful in discovery?

Answer 26

Yes, but must refine exactly what you are looking for

Question 27

How can screening assays be clouded?

Answer 27

Interference of compounds inc:

• Optical interference
• Reactions
• Aggregates
• Pan Assay Interference Compounds (PAIN)

Question 28

How can you prevent screening assays from being clouded?

Answer 28

• Known problem compounds can be filtered out based on substrucure

Question 29

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

Answer 29

It will be context dependent

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