Lecture 2 - Drug Discovery and Drug Development Flashcards
(16 cards)
Examples of 3 naturally occurring drugs and their origins
- Morphine from opium
- Cocaine from coca leaves
- Quinine from the bark of the cinchona tree
What is a lead compound?
The active principle isolated from the plant.
What are the 6 substages in Stage 1 of Modern Drug Discovery?
i) Choose disease of importance to the western world
ii) Choose drug target - receptors (use agonist/antagonist), enzymes (use enzyme inhibitor), carrier proteins
iii) Identify bioassay (measurement of concentration/potency of substance by its effect on living cells/tissues)
iv) Find ‘lead compound’ - from natural sources or combinatorial library
v) Isolate and purify lead compound if necessary
vi) Determine structure of lead compound
What are the 6 substages in Stage 2 of Modern Drug Discovery?
vii) Identify Structure-Activity Relationships (SARs)
viii) Identify pharmacophore (minimal part of structure which makes biological activity known)
ix) Improve pharmacokinetic properties (ADME)
x) Patent drug
xi) Study drug metabolism: ADME
xii) Test for toxicity
What are the 3 substages of Stage 3 Modern Drug Discovery?
xiii) Design a manufacturing process
xiv) Carry out clinical trials
xv) Market the drug
What are the 4 features of in vitro testing?
- Involves isolated tissue/cells/enzymes in cultured solutions in test tube
- Enzyme inhibitors can be tested on purified enzyme in solution
- Receptor agonists/antagonists can be tested on isolated tissues/cells that express target receptor on surface
- Instead of investigating ability of drug to occupy receptor, physiological endpoint can be measured e.g. examining effect of drug on inhibition of contraction of bronchial smooth muscle i.e. bronchodilator activity
What does high throughput screening involve? What are the requirements?
Automated testing of 1000s of compounds against 30-50 biochemical targets. Test must be easily measured e.g. enzyme catalysed reaction that produces colour change.
What are the 4 features of in vivo testing?
Involves inducing a clinical condition in an animal to produce observable symptoms.
E.g. in antimalarial drug discovery mice are infected with parasites.
Antimalarial activity of potential drug can be assessed by either the ability of drug to clear parasites from bloodstream of infected animals or the ability of the drug to prolong mouse survival
Genetics has also had an impact since it’s possible to produce transgenic animals e.g. replace mouse genes with human genes
What are the 8 methods in discovering a lead compound?
- Medical folklore
- Random screening of synthetic “banks”
- Existing drugs - ‘Me too drugs’
- Starting from the natural ligand
- Combinatorial chemistry
- Computer aided design
- Computer based searching of structural data banks
- Screening natural materials
What are 2 of the most important natural products discovered for the treatment of disease?
Antibacterial penicillin and antimalarial quinine
What is the mechanism of action of penicillin?
- Involves inhibiting bacterial cell wall synthesis
- Enzyme -OH –> (irreversible acylation) O-Enzyme
- Enzyme targeted by penicillin is responsible for cell wall synthesis
- Holes develop in cell wall that lead to cell content leakage and death of bacteria
- Penicillin is bactericidal
What are the desirable and undesirable properties of penicillin?
Desirable:
- Active against gram positive and some gram negative bacteria
- Not toxic and very selective - amongst the safest drugs discovered
Undesirable:
- Not active over a wide range (spectrum) of bacteria
- Ineffective when taken orally (stomach decomposition)
- Sensitive to all known beta-lactamases (enzymes produces by bacteria which inactivate penicillin - important resistance mechanism)
What are the 4 pharmacophoric groups for penicillin? (groups of the molecule that are crucial for activity)
- Bicyclic ring
- Beta-lactam ring
- Carboxylic acid
- Side-chain amide
What are the 3 main reasons why penicillin G is so acid sensitive?
- Bicyclic ring imparts large angle and torsional strain. Acid catalysed ring opening relieves strain.
- Carbonyl group in beta-lactams very reactive. Unusual as carbonyl groups in tertiary amides usually very resistant to hydrolysis due to resonance (not the case here as ring would be too strained, so resonance form doesn’t form)
- Side-chain can act to cleave beta-lactam ring by attacking at its carbonyl C which kicks out C-N bond, breaking open ring (self destruct mechanism)
What is the solution to the acid sensitivity problem of penicillin?
To reduce self-destruction of beta-lactam by chemical substitution in the acyl side chain
- If EWG attached to carbonyl oxygen, reduces tendency of carbonyl O to act as nucleophile.
What is the solution to penicillin’s sensitivity to beta-lactamases?
To incorporate a large side chain that acts as a shield to prevent lactamase mediated cleavage.
