Pharmacology L1, L3 and L4 Flashcards
Which of these is the chemical, generic and trade name?
N-acetyl-para-aminophenol, paracetamol/acetaminophen, panadol
N-acetyl-para-aminophenol = chemical
Paracetamol/acetaminophen = generic (mix of chemicals)
Panadol = trade
What are main targets of drugs?
Receptors (GPCRs in particular), enzymes, transporters, channels
What is the most common receptor involved in drug signalling pathways?
GPCR receptors
What are the 8 steps of the drug discovery process?
When does discovery end and development start?
When do we obtain our lead and candidate?
Target selection –> target validation –> lead discovery –> lead optimisation –> pre-clinical development –> clinical development –> regulatory approval –> release to market
Discovery ends after lead optimisation yields candidate drug(s).
Lead is obtained after “lead discovery” phase; candidate obtained after “lead optimisation”
What are the 3 methods of identifying drug targets?
Analysis of pathophysiology (e.g. we want to find a drug for depression) (forward approach: disease to target to drug)
Analysis of mechanism of action of existing drugs (e.g. a drug we know works, but we don’t know how) (backwards approach: drug to target)
Genomic approaches (e.g. identify errors in transcription and translation; search for druggable genes)
What are “druggable genes”?
Genes which code for proteins that are involved in disease and can be targeted by drugs
How was fluoxetine discovered?
Analysis of pathophysiology (forwards approach) –> disease to target to drug –> researchers noticed that there existed a serotonin transporter on pre-synaptic neurons which decreased serotonin in synaptic cleft –> based on physiology of neuron, researchers created transporter inhibitor, Fluoxetine
Similar story with ACE inhibitors –> studies of renin-angiotensin system in hypertension made researchers select angiotensin converting enzyme as the target for drug action
How were benzodiazepines discovered?
Benzodiazepines just worked for anxiety and sleep disorders, so physicians prescribed them without question their mechanism of action –> later discovered GAMA receptors were their targets –> similar drugs developed upon discovery of GAMA receptors
How can we validate a target once we have found it?
KO the gene coding for the target protein in animal models; express the gene ex-vivo in a cellular system with siRNA (e.g. ASOs)
What are the 3 consecutive steps we can take for finding lead compounds during the “lead discovery” phase when starting from nothing but a target?
- Screen a bunch of compounds in chemical library
- Identify potential leads, called hit candidates (primary hit candidates, validated hit candidates)
- validate those hit candidates, obtain around 3 lead compounds
What is the difference between a hit candidate and drug candidate/candidate drug?
Hit candidate is a potential chemical that could turn out to be a lead. Drug candidates are leads which have been optimised to enter pre-clinical trials.
Hit candidates themselves are NOT leads.
What are the 4 sources of new drugs?
- screening chemical libraries (e.g. high throughput screening)
- rational drug designing
- serendipity
- screening natural products
Explain the 4 types of rational drug design?
RDD is about determining the structure and function of a target receptor/molecule and using this information to develop drug treatments instead of relying on serendipity.
- Designing brand-new drug based on pathophysiology of disease (e.g. identification of ACE enzyme involved in renin-angiotensin; generating drug derived from viper venom, modifying it with medicinal chemists, and generating ACE inhibitors)
- exploiting side effects (e.g. sulphanilomide; extracting the part of a chemical that elicits a side effect, modifying it and marketing it as a drug for some other condition)
- Quantitative structure activity relationships, QSAR (using a virtual “screening” tool to assess the structures and activities of chemicals in library and matching them to your receptor)
- structure-based design (virtual assessment of receptor structure + identification of binding pockets/surface features that can be targeted by drug)
What are primary hit candidates?
Chemicals that have affinity for receptor, but no efficacy.
They are what you get after that first round of primary screening of chemical libraries.
What is high throughput screening?
Main method of screening chemical libraries for possible lead compounds for our target; 1000-5000 compounds screened against target simultaneously in cell-based assay
How many compounds/chemicals from our chemical library can be screened against our target simultaneously?
1000-5000
Lead discovery: How many compounds do we screen? How many primary hit candidates do we get? How many validated hit candidates do we get? How many lead candidates do we end up with?
- 100,000 - 1,000,000 compounds/chemicals from chemical library are screened
- 100 - 1,000 primary hit candidates
- 10 validated hit candidates
- 3 lead compounds
How do we go from 100-1,000 primary hit candidates to our 10 validated hit candidates? I.e. how do we validate our primary hit candidates. What are the key features of a validated hit candidate
Look for affinity, efficacy (whether it activates/inhibits receptor) and selectivity (chose compounds that have minimal off-target effects)
Validated hit candidates (x10) have the following features:
- Activity at receptor as inhibition or activation
- drug-like properties (e.g. low MW <500, clogp <5, aromatic ring in structure)
- defined, novel structure
VHC are not “drugs” because aren’t optimised for selectivity, toxicity and ADME properties in humans yet
To get from VHC to lead, we send the VHC to medicinal chemists for SAR modifications to improve pharmacokinetic properties and reduce toxicity
What are the requirements for a compound to be classified as a “drug”?
Drugs (i.e. candidate drugs) are leads which have been optimised and are in pre-clinical development –> have had selectivity, efficacy, toxicity, ADME tests done
What is clogP?
A measure of lipophilicity. Optimal is <= 5 but not too low –> high clogP means lipophilic… if too low then drug is hydrophilic, and will not be able to enter into bloodstream and be distributed