topic 13 - drug design and discovery Flashcards
what is a drug?
“a chemical substance used to prevent or cure disease”
or
“a substance which has a physiological effect when introduced into the body”
drug discovery pipeline
source of compounds
pool of potential drug molecules
hit compounds
lead compounds
clinical candidate
preclinical development
manufacturing
clinical trials
marketing, use and monitoring.
what is fumaria officinalis - drug fumitory?
Fumaria officinalis – “drug fumitory”
Used medicinally across Europe to treat eyes, as a digestive aid, a diuretic, for skin blemishes, and more…
Contains fumaric acid – named after the plant
Fumaric acid was later found to be active against psoriasis
Dimethyl fumarate (an analogue) is more effective, and an approved drug against psoriasis and multiple sclerosis
Its mechanism is still not clear.
what is Artemisia annua - sweet wormwood?
Used medicinally in China against malaria symptoms
Recommended by Li Shizhen in 16th Century pharmacopoeia
Chinese scientists screened a list of 2000 traditional medicines in the 70s
Tu Youyou discovered the compound artemisinin
Best extraction method is similar to traditional preparation
Game-changing antimalarial.
what is centella asiatca (gotu kola) and madecassic acid (MA)?
Centella Asiatica (Gotu Kola)
Popular medicinal herb in SE Asia
Used for: High blood pressure, arthritis, wound healing, anti-ageing
Madecassic acid (MA): Natural product from C. Asiatica
Antiproliferative activity against liver cancer
Chemical derivatives improved potential
Liver cancer issue in Vietnam – 25,000 death per year
Project Aim: Bring MA derivatives forward as potential new therapeutics against liver cancer, which could be produced within Vietnam
what are the benefits of natural products?
All natural products have some kind of biological activity already
Could be produced by agricultural or biotechnological methods
Provides access to unusual/diverse structures.
what are the drawbacks of natural products?
Can be difficult to obtain in high yields
Total synthesis challenging
Compounds are not optimised
Could be allergens
what is phenotypic drug discovery / phenotypic screening?
Phenotypic screening: approaches looking only at the final effect of a drug, rather than relying on knowledge/hypotheses of how the drug works
This has historically been the way in which drugs were discovered, and it is still useful
Screening of natural products has given us paclitaxel, a key cancer treatment, isolated from the bark of the pacific yew tree.
Phenotypic screening can also work for large libraries of synthetic compounds (i.e. not natural products).
what is target based drug discovery?
Most modern industrial drug discovery is target-based
This means that a certain biomolecule has been identified as problematic, and a drug will be developed to change its behaviour, with the aim of certain final effect.
Requires knowledge of biochemistry in question
A good target should be efficacious, safe, and “druggable” = readily influenced by small molecules.
target based drug discovery pt 2
Targets must be selected well to maximise activity and minimise side-effects
Biology usually has more than one way to send the same message
One protein may interact with many others, some beneficial, some harmful.
what are the benefits of designed synthetic compounds?
Synthesis straightforward (comparatively)
Readily modified at any point to tune properties
Mechanism of action usually well understood.
what are the drawbacks of designed synthetic compounds?
Limited to molecules which are easily made
Chirality and larger 3D structures rarer
Does not work so well on proteins without small molecule binding pockets.
what is screening and selection?
Unbiased approaches take a huge random library (small drug-like molecules, fragments of drug-like molecules, peptides, oligonucleotides, other oligomers).
Screening: measure each molecule’s interaction with the target.
Selection: use some affinity measurement to separate binders from non-binders
what are the benefits of screening and selection?
Test millions of molecules at once
Could uncover unexpected activities
Exploit molecular biology techniques – phage display of peptides, PCR, sequencing, etc.
Target any protein with larger molecules
what are the drawbacks of screening and selection?
Might not find any good hits – even a library of >1 million compounds could be poorly designed
Limited to libraries which can easily be made
Larger molecules may have trouble getting through membranes etc.
