WEEK 2 Flashcards
What does High Throughput Screening (HTS) ?
HTS screens a library (collection) of compounds for preliminary in vitro activity- hits
What can hits be transformed to ?
We look to transform hits into leads (promising candidates)
What can lead then be progressed to ?
Lead can then be optimised to progress to clinical trials
Why do we need to avoid “phony hits/frequent hitters” or false positives in an HTS screen ?
As we can spend time/money and not progress to a lead
Such promiscuous hits have poor selectivity, so display ?
Little SAR (Structure Activity Relationship) so must be avoided in libraries
What are Pan Assay Interference Compounds (PAINS) ?
They are chemical compounds that often give false positive results in high-throughput screen
What do Agonist give ?
Biological effect at a receptor (often G protein coupled receptor)
What do Antagonists do ?
They can block/compete with agonist to occupy receptor, but not give an effect
What is Sumatriptan ?
- 5HT1A/1D agonist
- Migraine
What is Ondansetron ?
- Anti emetic 5HT3 antagonist
- Helps patients tolerate chemotherapy by reducing side effects
What is Buspirone ?
- 5HT1A
- Antagonist
- Anxiolytic
What do highly lipophilic first-generation antihistamines penetrate ?
- The CNS leading to sedation
- Used to treat itching, allergies, motion sickness
Explain 2nd Generation H1 antagonist ?
Don’t cross BBB significantly so lower CNS effects, more polar, less “fatty”. LogP can determine BBB penetration.
What does Cholecystokinin Antagonist (CCK1) ?
To treat panic attacks
What is Pharmacophore ?
Important binding groups and their relative positions
Lead compounds from natural sources are often complex and difficult to synthesise. What does simplifying the molecule do ?
It makes the synthesis of analogues easier, quicker and cheaper
Explain the simpler structures binding, activity, selectivity and toxicity ?
- 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
Explain different methods that can be done for simplification?
- Retain pharmacophore (biologically relevant groups needed for biological activity)
- Remove unnecessary functional groups
- Remove excess rings
- Remove asymmetric centres SOMETIMES beneficial (as in all drug discovery programmes, there isn’t a one size fits all)
Lipinski’s rule of five: For oral availability, we need:
- MW<500
- logP<5
- HBDs (OH, NHs) <5
- HBA (sum of O, N atoms) <10
What are the Verber rules?
- Good oral bioavailability
- ≤10 rotatable bonds
- PSA ≤ 140Å2 (≤ 12 HBD, HBA)
What is Antabuse used for?
- 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)
What was Clonidine originally developed as ? but what is it now used for ?
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
What is Mustard gas used for?
- 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
What is the Ames test used for?
Looks at mutagenic properties of a compound. We can do this at an early stage to avoid costly development of a carcinogenic compound
Explain HERG channel ?
- 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
What is Fexofenadine ?
Hayfever/allergy drug
What is Terfenadine ?
Prodrug of fexofenadine; metabolised by CYP3A4
What is a contraindication for the metabolisation of Terfenadine ?
- Grapefruit juice (a known CYP3A4 inhibitor)
- So drinking juice will lead to toxic build up of terfenadine and Herg effects
Why would Terfenadine be withdrawn ?
Due to HERG channel action; cardiotoxicity. Replaced by fexofenadine (a productive metabolite)
What is Maraviroc ?
A CCR5 antagonist and an anti HIV drug candidate
