Drug Discovery 1&2

Question 1

What are the 3 main sources of drugs?

Answer 1

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

Question 2

How long is the general drugs discovery pipeline?

Answer 2

25

Question 3

What is IC50?

Answer 3

Te concentration of drug where you get 50% inhibition

Question 4

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

Answer 4

IC50 = 1µM

Question 5

What is a Hit?

Answer 5

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

Question 6

What is the target?

Answer 6

protein or other molecule whose activity is to modified

Question 7

What is a lead?

Answer 7

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

Question 8

What is an optimised lead?

Answer 8

• 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

Question 9

What is clinical phase 1?

Answer 9

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

Question 10

What is clinical phase 2?

Answer 10

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

Question 11

What is clinical phase 3?

Answer 11

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

Question 12

What is the regulation phase of the drug discovery pipeline?

Answer 12

Approval for drug to be used and marketed

Question 13

What is the ‘sales’ phase?

Answer 13

Also known as phase IV - monitoring side effects over years

Question 14

What is the rough cost of the drug discovery pipeline?

Answer 14

Between $500 million to $1.5 billion

Question 15

What is attrition rate?

Answer 15

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

Question 16

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

Answer 16

Clinical phase 3

Question 17

What is Eroom’s Law?

Answer 17

The cost per drug production is increasing as efficiency decreases.

Question 18

What does AMDET stand for?

Answer 18

Absorption
Distribution
Metabolism
Excretion
Toxicology

Question 19

How many drugs is ADMET RESPONSIBLE FOR THE FAILURE OF?

Answer 19

30%

Question 20

What is pharmacokinetics?

Answer 20

What the body does to the drugs

Question 21

What is pharmacodynamics?

Answer 21

What does the drug do to the body

Question 22

What are lipinsky’s rules of 5 for?

Answer 22

Guidelines for a good drug

Question 23

What are lipinsky’s rules of 5?

Answer 23

• 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

Question 24

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

Answer 24

10^9-10^13

Question 25

How many drugs are in circulation?

Answer 25

≤ 1,000,000

Question 26

What is high throughput screening?

Answer 26

Assaying thousands of drugs for effectiveness.

Question 27

What are the different plates numbers?

Answer 27

96 384 1536 (or one eppendorf tube)

Question 28

What is scaffold hopping?

Answer 28

Where you change the structure but maintain the primary chemical features

Question 29

What is Pharmacophore?

Answer 29

Set of molecular features arranged in relative spatial orientation

Question 30

What is QSAR?

Answer 30

A quantitative connection between chemical structure and biological activity

Question 31

What is Ki?

Answer 31

Inhibition constant

Question 32

What is comfa?

Answer 32

3D QSAR - see condensed notes

Question 33

What is DUD?

Answer 33

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

Question 34

What is an enrichment factor?

Answer 34

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

Question 35

What is R.M.S.D?

Answer 35

Deviation from perfect bond angles and bond lengths during docking

Question 36

What is POSE?

Answer 36

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

Question 37

How are docking algorithms often characterised?

Answer 37

By the degrees of freedom they acknowledge (DF)

Question 38

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

Answer 38

This would require a lot of computational time

Question 39

What is a simple way to identify possible binding sites?

Answer 39

Manually identify large clefts

Question 40

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

Answer 40

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

Question 41

What might be considered in a docking algorithm scoring mechanism ?

Answer 41

Van der waals Electrostatics sometimes hydrophobic affect Some use a softer scoring to prevent omitting potential hit s

Question 42

What is AutoDock Vina?

Answer 42

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

Question 43

What is benchmarking virtual screening?

Answer 43

Analysis of whether an algorithm predicts correct POSE and binding site

Question 44

What is a blind trial?

Answer 44

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

Question 45

Sicking often fails. Why is it still worth performing?

Answer 45

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