WEEK 2

Question 1

What does High Throughput Screening (HTS) ?

Answer 1

HTS screens a library (collection) of compounds for preliminary in vitro activity- hits

Question 2

What can hits be transformed to ?

Answer 2

We look to transform hits into leads (promising candidates)

Question 3

What can lead then be progressed to ?

Answer 3

Lead can then be optimised to progress to clinical trials

Question 4

Why do we need to avoid “phony hits/frequent hitters” or false positives in an HTS screen ?

Answer 4

As we can spend time/money and not progress to a lead

Question 5

Such promiscuous hits have poor selectivity, so display ?

Answer 5

Little SAR (Structure Activity Relationship) so must be avoided in libraries

Question 6

What are Pan Assay Interference Compounds (PAINS) ?

Answer 6

They are chemical compounds that often give false positive results in high-throughput screen

Question 7

What do Agonist give ?

Answer 7

Biological effect at a receptor (often G protein coupled receptor)

Question 8

What do Antagonists do ?

Answer 8

They can block/compete with agonist to occupy receptor, but not give an effect

Question 9

What is Sumatriptan ?

Answer 9

• 5HT1A/1D agonist

- Migraine

Question 10

What is Ondansetron ?

Answer 10

• Anti emetic 5HT3 antagonist

- Helps patients tolerate chemotherapy by reducing side effects

Question 11

What is Buspirone ?

Answer 11

• 5HT1A
• Antagonist
• Anxiolytic

Question 12

What do highly lipophilic first-generation antihistamines penetrate ?

Answer 12

• The CNS leading to sedation

- Used to treat itching, allergies, motion sickness

Question 13

Explain 2nd Generation H1 antagonist ?

Answer 13

Don’t cross BBB significantly so lower CNS effects, more polar, less “fatty”. LogP can determine BBB penetration.

Question 14

What does Cholecystokinin Antagonist (CCK1) ?

Answer 14

To treat panic attacks

Question 15

What is Pharmacophore ?

Answer 15

Important binding groups and their relative positions

Question 16

Lead compounds from natural sources are often complex and difficult to synthesise. What does simplifying the molecule do ?

Answer 16

It makes the synthesis of analogues easier, quicker and cheaper

Question 17

Explain the simpler structures binding, activity, selectivity and toxicity ?

Answer 17

• Simpler structures may fit the binding site easier and increase activity
• Simpler structures may be more selective and less toxic if excess functional groups are removed

Question 18

Explain different methods that can be done for simplification?

Answer 18

1. • Retain pharmacophore (biologically relevant groups needed for biological activity)
   • Remove unnecessary functional groups
2. • Remove excess rings
3. • Remove asymmetric centres SOMETIMES beneficial (as in all drug discovery programmes, there isn’t a one size fits all)

Question 19

Lipinski’s rule of five: For oral availability, we need:

Answer 19

• MW<500
• logP<5
• HBDs (OH, NHs) <5
• HBA (sum of O, N atoms) <10

Question 20

What are the Verber rules?

Answer 20

• Good oral bioavailability
• ≤10 rotatable bonds
• PSA ≤ 140Å2 (≤ 12 HBD, HBA)

Question 21

What is Antabuse used for?

Answer 21

• Used as an additive in the rubber industry - workers who used it didn’t like the taste of alcohol. It prevents the correct oxidation of alcohol in the liver and leads to the build up of acetaldehyde (CH3CHO)

Question 22

What was Clonidine originally developed as ? but what is it now used for ?

Answer 22

Originally developed as a nasal vasoconstrictor. Clinical trials showed it led to a drop in blood pressure so it became used as an antihypertensive agent

Question 23

What is Mustard gas used for?

Answer 23

• A WW2 shipment exploded in Italy and people exposed to the gas displayed a lower white blood cell count
• Leukaemia involves excess white blood cell formation, hence mustard gas was modified into anti-leukaemia

Question 24

What is the Ames test used for?

Answer 24

Looks at mutagenic properties of a compound. We can do this at an early stage to avoid costly development of a carcinogenic compound

Question 25

Explain HERG channel ?

Answer 25

• Human ether-a-go-go related gene!!! (K+ channel)
• Associated with long QT Syndrome, arrhythmia and sudden cardiac death.
• Cisapride and terfenadine withdrawn due to HERG problems

Question 26

What is Fexofenadine ?

Answer 26

Hayfever/allergy drug

Question 27

What is Terfenadine ?

Answer 27

Prodrug of fexofenadine; metabolised by CYP3A4

Question 28

What is a contraindication for the metabolisation of Terfenadine ?

Answer 28

• Grapefruit juice (a known CYP3A4 inhibitor)

- So drinking juice will lead to toxic build up of terfenadine and Herg effects

Question 29

Why would Terfenadine be withdrawn ?

Answer 29

Due to HERG channel action; cardiotoxicity. Replaced by fexofenadine (a productive metabolite)

Question 30

What is Maraviroc ?

Answer 30

A CCR5 antagonist and an anti HIV drug candidate