topic 14 - target based drug discovery, and administration Flashcards
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
fitting the drug to the target
How will you find a molecule for a particular target?
One starting point would be variation of the molecule the protein binds in nature – either the enzyme
substrate or the molecule which binds to a receptor
Modifications can make the drug stimulate the receptor’s signalling (agonist) or disrupt it (antagonist) depending on how it binds.
Crystal structures of the target proteins can provide information about where modifications might be effective.
benefits of designed synthetic compounds
Synthesis straightforward (comparatively)
Readily modified at any point to tune properties
Mechanism of action usually well understood
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.
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
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.
what are biological assays?
Choice of bioassay is crucial – must be quick, simple, relevant.
Most drugs fail – best strategy is “fail early, fail cheap”
In vitro = on isolated cells, tissues, proteins
In vivo = on entire organisms (no difference if you’re looking at bacteria!)
In vitro is usually preferred for initial tests because it is cheaper, quicker, less controversial, and can be automated. This will test whether the drug engages its target, in what fashion, whether it changes the target’s activity, and whether it kills cells. Often colourimetric of fluorescent output.
what is pharmacology?
Pharmacokinetics (How does the body deal with drugs?)
Fate of drugs once they have been ingested
Variability of response between patients
How drugs move through the body in the processes of
absorption, distribution, metabolism, and excretion - (ADME).
Pharmacodynamics (What effect drugs have on the body?)
Is the study of how a drug binds to its binding site
the drug not only has to bind to its target, it has to reach it in the first place
For an oral drug that involves a long journey with many hazards to be overcome.
administration of drugs
Drugs may be:
acidic
basic
neutral
small organic molecules
large polymers
other compounds with complex chemistries
what does the route of administration depend on?
Physical & chemical property of the drug (e.g. pH, solid, liquid, solubility)
Site of desired action – localised or generalised
Effect of digestive juices and first pass metabolism of drug
Accuracy of dosage required
Condition of the patient e.g. unconscious, vomiting, etc.
what are the local routes of examination?
Topical – external application of the drug to the surface e.g.
lotion
cream powder
Spray
Drops
Deeper Tissues - certain deep areas can be approached by syringe and needle e.g.
intra-articular (joint)
intra-medullary (bone marrow or spinal cord)
Intrathecal pump (spinal fluid)
Arterial Supply – Closed intra arterial injection
e.g. angiography and anti-cancer drugs
what are the systemic routes of administration?
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart.
five routes to the systemic sytem:
oral
sublingual
inhalation
intradermal and subcutaneous
intravenous
what is sublingual?
Kept under the tongue or crushed and spread over the mouth. Absorption through mucous membrane with good access to arteries.
advantages
Rapid absorption (< 1 minute)
Liver is by passed – directly in the systemic circulation
Unconscious patients
disadvantages
Only lipid and saliva soluble drugs
Uncooperative patients
Irritate the mucosa
advantages and disadvantages of INTRAVENOUS?
advantages:
Quick action – good for emergencies
Desired concentration easily obtained
No hepatic first pass metabolism
Unconscious and uncooperative patients.
disadvantages:
Costly – special apparatus
Local irritation
Self medication not possible
Action cannot be stopped
Aseptic and antiseptic measures must be maintained
Extravasation (escape of drug into tissue )may cause severe irritation
Onset of action between 15-30 seconds.
intradermal, subcutaneous and intramuscular
Intradermal
e.g. sensitivity tests
Subcutaneous
Self injection possible
e.g. insulin
Intramuscular
Thiethylperazine – (Torecan)
For nausea and vomiting
RNA vaccines
Onset of action between 10-30 mins.
