Toxicology🦠 Flashcards
What are 4 key strategies used to look for new drugs?
- follow-on compounds
- computational modelling + sequencing
- serendipitous discovery
- evergreening
What are follow-on compounds?
example?
- a drug originally discovered for one purpose, but found to be incredibly effective for another purpose
- e.g. sildenafil originally for CV issues, now treats erectile dysfunction
- i.e. luck method
What kinds of drugs are produced from serendipitous discovery?
- structurally similar to previously reported drug
- AKA “fast followers” or “me too” drugs
serendipitous discovery drugs have same mechanism as which?
2 examples?
- Same mechanism as the prototype drug but different enough to be considered novel
- e.g. captopril, enalapril
Why are drugs found by serendipitous discovery appreciated by regulators?
- provide professionals & patients with multiple options
- contribute to keeping prices low
What kind of drugs are discovered through evergreening?
- Extreme form of a “me too” drug
- Practically extending the duration of a patent with minimal chemical intervention or changes
computational modelling + sequencing: name of project used and what does the process achieve/entail?
human genome project
increasing num of solved protein x-ray crystal structures
whens computational modelling + sequencing ideal/used?
when step 1: follow on compounds from natural drug doesnt work to get lucky
computational modelling and sequencing requires understanding of what?
the target!
How does esomeprazole relate to omeprazole, and how was it discovered? (3)
- pure enantiomer of omeprazole where alcohol points forwards
- discovered through evergreening
- improved properties: PK profile, resistance to metabolism, conductive to a longer duration
Process to find new drugs
Where do we start when discovering new drugs? (hint: t_ v_, h_ i_)
target validation: explore relationship between pharmac.l modulation of a target and pathological condition. Correlation is not enough… causality must be established
hit identification: chemically accessible (synthesised easily) compound displaying initial activity towards target; can be done individually in lab
What are the characteristics the of the ‘hits’ identified?
affinity? MW? cLogP? number of rings? HBAs? HBDs?
- moderate affinity (nM - µM)
- low MW (150 < 400)
- cLog P < 4.5
- 1-4 rings
- <8 HBA
- <5 HBD
where to look for new drugs? 3 designs
rational design
high throughput screening
natural products
What type of design is where we look to find hits?
rational design
whats rational design based on and what does it utilise?
- can be based on physiological binders (substrates, co-factors)
- starts w molecule known to be active, attempts to improve on it
- Generally utilises structural information to improve ligand interactions in binding site
- attempts to improve what we can do at binding site using structural information
- e.g. protein kinases are target, so develop sunitinib similar to ATP, its substrate
and Ad -> propanolol
Instead of rational design, what could you use when you don’t know much about your target?
high-throughput screening - screening as many compounds as possible and hope to get lucky
What are 2 types of screens used in high throughput screening?
- unselected screens
- selected (directed) screens
What are the disadvantages of using unselected screens in high-throughput screening?
• Hit rates likely to be ~ 1%
• need to screen millions of compounds -> decent num of hit families to follow up
• Limited by budget, time, resources and intrinsic throughput:
limited to a number of compounds at a single concentration; generates noise
What are selected (directed screens) used in high-throughput screening?
- sometimes enough info about target to inform screening
- combo of rational design and unselected screening
What are the advantages of selected (directed) screens?
- faster
- reduces costs
- easier identification of true activity
high throughput screening:
2. selected (directed) screens
num of compounds large -> small
gradual scale
diversity based property based (rational design): target class/ privileged strucs pharmacophore based libraries target specific libraries
What are natural products?
3 examples
- also looked at for when discovering new drugs
- chemicals produced by organisms (commonly fungi, bacteria, plants)
- e.g. salicylic acid, geldanamycin, paclitaxel (Taxol)
Why are natural products difficult to synthesise?
- they are often very complex structures, with multiple stereocentres and macrocycles
- this makes it difficult to control the synthesis
What are PAINs?
Pan-Assay Interference Compounds:
- Positive hit compounds which turned out to be due to non-specific binding (artefacts)
- false positives (e.g. quinones)
- Compounds consistently identified as promising hits against different proteins
- Defined structures, covering several chemical classes