Drug Discovery

Question 1

What are the four main sources of drug leads?

Answer 1

1. Natural Products
2. Existing/’me-too’ drugs
3. Phenotype Screening
4. Target-based Screening

Question 2

What is the main disadvantage of sourcing drug leads from natural sources?

Answer 2

You can obtain many different compounds from natural products so it can be difficult to determine which compound is the active one.

They also tend to be structurally complex and would be costly to replicate in the lab.

Are often highly toxic and hence unsuitable for use as a drug unless we synthesise analogues.

Question 3

What natural products can drugs be sourced from?

Answer 3

1. Plant sources
2. Animal sources
3. Marine sources: tend to be richer in bioactive compounds if the organism is immobile.
4. Microorganisms

Question 4

Existing/’Me Too’ Drug

Answer 4

A drug with a similar structure and activity to an existing one, modified just enough to escape patent restrictions but still functionally the same.

An example includes proton pump inhibitors.

Question 5

Chiral Switches

Answer 5

Some drugs can be racemates, i.e. they may have two enantiomers, the chiral switch is the enantiomer of an existing drug that was found to have medical purposes. Drugs must be marketed as a single enantiomer or have determined that both enantiomers are safe.

Question 6

Phenotype Screening

Answer 6

Testing drugs on a living organism to observe changes in the behaviours or form of the organism.

Can be in vitro (quick, less expensive and ethical) or in vivo (expensive, slow, and ethically fraught).

An example is viagra, clinical tests for its efficacy at treating angina revealed it’s usefulness as a treatment for erectile dysfunction.

Question 7

Target-based Screening

Answer 7

The cause of the diseased state is first identified and then the target (in vitro) will be used to see if the drug is effective.

DISADVANTAGE: Assumes the cause of disease is known, if this knowledge is incorrect the drug will likely not succeed.

Eg. Captopril - studies of snake venom leads to discovery of bradykinin, research on developing a drug that inhibits the converting enzyme begins.

Question 8

What are the five main sites for drug action?

Answer 8

1. Enzymes
2. Receptors
3. Cell replication and protein synthesis
4. Transporter systems
5. Storage sites

Question 9

What are the three types of screening methods?

Answer 9

1. Random Screening: It is not known what drug would have the desired activity, so all the compounds in the drug library are tested against the target.
2. Focussed Screening: Drugs (analogues) with a vague resemblances to weakly active compounds are tested, has better hit rate than random screening.
3. High-Throughput Screening: a large number of compounds are tested over a large number of biological targets using robotics and miniaturised in vitro testing techniques.

Question 10

Prodrugs

Answer 10

Structurally modifying an active drug that is designed to improve a drug property that limits its pharmacokinetics and target exposure - it is converted in vivo to release the active drug.

Question 11

What prodrug strategies are there?

Answer 11

1. Increasing permeability: must mask polar functional groups to enhance lipophilicity but be able to hydrolyse rapidly.
2. Increasing solubility: non-ionisable promoities like glycol improve 2 fold, ionisable promoities like phosphate are highly effective.
3. Reducing metabolism: mask labile functional groups.

Question 12

Types of Prodrugs

Answer 12

1. Carrier-linked: The active drug is linked to a carrier group (non-toxic, biologically inactive) that can be removed enzymatically.

a) Bipartate: drug + carrier
b) Tripartate: drug + linking group + carrier
c) Mutual: drug + drug

2. Bioprecursors: In vivo chemical modification (typically oxidation or reduction) allows the prodrug to produce its effect.