Lead Compounds Flashcards
What is the progression of a drug?
Target Identification
Lead identification
SAR (structure activity relationship), Design and synthesis.
Formulation delivery
Toxicology
Clinical Trials
Patients
What does formulation delivery involve?
Checking its bioavailability –> pill more ideal than IV.
Potent direct to target so it doesn’t harm rest of body.
What is toxicology?
What metabolism does to the drug. Animal testing to human testing.
How can targets be identified?
Molecular biology techniques.
Identification of drug targets.
High throughout screening
Human genome project
What is the process of target identification?
Start with single target. (usually enzymes).
Enzyme or protein-protein interaction or receptor.
Target must be validated. (Long pharmacology process if stop does it repair disease state).
Develop a method for identifying molecules that bind/inhibit/activate.
Develop a high-throughput screen (can we screen a lot of compounds).
How do you validate a target?
Knockouts - usually mice in which the gene is deleted.
SiRNA
CRISPR/Cas - a type of molecular knockout.
Antisense - RNA targeted oligonucleotide - target RNA to stop proteins being created.
Small molecules - Which stop proteins from doing its action.
What is a lead compound?
A molecule with the desired biological activity. EG enzyme inhibition, receptor binding (antagonist and agonist), receptor maybe a protein/nucleic acid.
Prototype for eventual drug- study and develop analogues will lead to final marketable drugs.
What is a lead compound not?
It isn’t necessarily a “druggable” compound.
It may not be very active.
It may not be bioavailable.
It may generate lots of side effects.
Where can lead compounds come from?
- Natural products (eg plants & fungus).
- Medical folklore - ethnobotany (traditional eg use of mushrooms).
- **Screening synthetic libraries **(pharmaceutical companies have libraries they go through to see if any good compounds).
- Existing drugs (drugs exist with ideal affect).
- Combinational synthesis (not popular - put reagents in big pot to see what comes out).
- Natural substrate (eg find enzyme with similar affect you want and create drug)
- Computer Aided design (Popular - model it)
- Serendipity (luck)
What is an example of natural products?
Doxorubicin - antitumor anthracycline. Used in the clinic but limited by cardiac side effects.
—> Mitoxantrone - Synthetic anthraquinone. Used in the clinic but limited by toxic side effects but not cardiac.
—-> AQ4N - Synthetic anthraquinone. Prodrug. Currently in phase II clinical trial - avoids toxic and cardiac side effects.
What is an example of ethnobotany?
Snowdrop (plant).
1950s - Pharmacologist noted locals rubbed on forehead.
‘52 - isolated galanthamine.
Treatment for poliomyelitis. Now is Alzheimers disease.
What are some examples of natural products (biological drugs)?
- Insulin
- Interferon
- Monoclonal antibodies. (Trastuzumab (Herceptin))
What are some examples of synthetic libraries?
May be patented for a different reason unrelated to what you need a lead compound for.
Eg Viagra (originally heart drug).
What is an example of existing drugs?
Thalidomide - originally drug for morning sickness, still used for leprosy treatment in some countries.
Analogues of it are being used to develop as anti-angiogenic agents in cancer chemotherapy.
What are analogues
In chemistry, analogs or analogues are compounds in which one/more individual atoms have been replaced, either with a different atom, or with a diff functional group. Also it can refer to a substance which is similar in structure to another substance.
