Drug Discovery 1&2 Flashcards

1
Q

What are the 3 main sources of drugs?

A
  • Natural compounds
  • Small molecules (made synthetically, e.g. Gleevec)
  • Recombinant products (i.e. monoclonal antibodies)
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2
Q

How long is the general drugs discovery pipeline?

A

25

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3
Q

What is IC50?

A

Te concentration of drug where you get 50% inhibition

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4
Q

What is the typical IC50 of an initial hit in the drug discovery pipeline?

A

IC50 = 1µM

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5
Q

What is a Hit?

A

Small molecule with some effect identified by biological and/or computational screening

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6
Q

What is the target?

A

protein or other molecule whose activity is to modified

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7
Q

What is a lead?

A

Chemical modification of a hit to enhance its effects and remove adverse effects in ADMET

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8
Q

What is an optimised lead?

A
  • Potency of IC50 <1nM
  • Selectivity of 1000 fold compared to similar receptor
  • Solubility of <1mg/ml
  • ADMET compliancy
  • Safety demonstrated in animal
  • Efficiency (Better than other drugs) in animal models
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9
Q

What is clinical phase 1?

A

Small no. of healthy people (20-80) to establish a safe dose

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10
Q

What is clinical phase 2?

A

Larger numbers of unhealthy patients (100-300) to firm up results from phase 1 and to establish level of effectiveness

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11
Q

What is clinical phase 3?

A

Thousands of unhealthy patients to prove drug is effective and identify side effects against placebo

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12
Q

What is the regulation phase of the drug discovery pipeline?

A

Approval for drug to be used and marketed

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13
Q

What is the ‘sales’ phase?

A

Also known as phase IV - monitoring side effects over years

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14
Q

What is the rough cost of the drug discovery pipeline?

A

Between $500 million to $1.5 billion

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15
Q

What is attrition rate?

A

The amount of molecules that are dropped during the drug discovery pipeline

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16
Q

Which is the most expensive phase of the drug discovery pipeline?

A

Clinical phase 3

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17
Q

What is Eroom’s Law?

A

The cost per drug production is increasing as efficiency decreases.

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18
Q

What does AMDET stand for?

A
Absorption
Distribution
Metabolism
Excretion
Toxicology
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19
Q

How many drugs is ADMET RESPONSIBLE FOR THE FAILURE OF?

A

30%

20
Q

What is pharmacokinetics?

A

What the body does to the drugs

21
Q

What is pharmacodynamics?

A

What does the drug do to the body

22
Q

What are lipinsky’s rules of 5 for?

A

Guidelines for a good drug

23
Q

What are lipinsky’s rules of 5?

A
  • Molecular weight ≤ 500 Da
  • Not to lipophilic ClogP ≤ 5.0 (lipophilicity)
  • Few H-bond donors (≤ 5)
  • Few H-bond acceptors (≤ 10)(sum of Ns and Os)

New additions:

  • Number of atoms between 20 and 70
  • At least one OH-group
  • Less than 8 rotatable bonds
24
Q

What are the estimated maximum number of drugs that can exist?

A

10^9-10^13

25
Q

How many drugs are in circulation?

A

≤ 1,000,000

26
Q

What is high throughput screening?

A

Assaying thousands of drugs for effectiveness.

27
Q

What are the different plates numbers?

A

96
384
1536
(or one eppendorf tube)

28
Q

What is scaffold hopping?

A

Where you change the structure but maintain the primary chemical features

29
Q

What is Pharmacophore?

A

Set of molecular features arranged in relative spatial orientation

30
Q

What is QSAR?

A

A quantitative connection between chemical structure and biological activity

31
Q

What is Ki?

A

Inhibition constant

32
Q

What is comfa?

A

3D QSAR - see condensed notes

33
Q

What is DUD?

A

A database of known decoys that allows you to identify decoys in dataset without further experiment

34
Q

What is an enrichment factor?

A

A way to evaluate the ability of identifying actives from inactives. % actives in top x%/%non actives/total molecules

35
Q

What is R.M.S.D?

A

Deviation from perfect bond angles and bond lengths during docking

36
Q

What is POSE?

A

The prediction of how the ligand is orientated in the binding site

37
Q

How are docking algorithms often characterised?

A

By the degrees of freedom they acknowledge (DF)

38
Q

Why in docking aren’t molecules alway considered to be entirely flexible?

A

This would require a lot of computational time

39
Q

What is a simple way to identify possible binding sites?

A

Manually identify large clefts

40
Q

What would a more complex geometric approach to identifying binding site be?

A

F-pocket - testing alpha sphere (sphere which can touch at least 4 atoms) that match the size of the ligand to identify possible binding sites

41
Q

What might be considered in a docking algorithm scoring mechanism ?

A

Van der waals
Electrostatics
sometimes hydrophobic affect

Some use a softer scoring to prevent omitting potential hit s

42
Q

What is AutoDock Vina?

A

It is a simplified scoring model hydrophobic & hydrogen bonding as well steric conditions.
Allows for rotation of bonds in ligand and side chain but not main chain

43
Q

What is benchmarking virtual screening?

A

Analysis of whether an algorithm predicts correct POSE and binding site

44
Q

What is a blind trial?

A

An interaction that as been determined but not published is tested in the algorithm for it’s accuracy of prediciton

45
Q

Sicking often fails. Why is it still worth performing?

A

It is very cheap and quick a large computer farm of 1000 computers can screen 1million molecules in 10 day