WEEK 9: DRUG TARGETS AND DRUG DESIGN Flashcards
What are the urgent level hazards in terms of highly resistant pathogens?
- clostridiodes difficile
- CRE (Carbapenam-resistant Enterobacteriaece)
- Drug resistant Neisseria gonorrhoeae
What is the concept of ‘One Health’?
- One Health concept recognises that the health of the human population is connected to the health of animals and the environment
- So we shouldn’t be giving the same antibiotics to animals that we take
Are the same antibiotic classes used in humans and farm animals?
- YES e.g. Chickens are given two antibiotics
What is the most deadly place for nosocomial infections?
- ICUs!
- Rely heavily on sanitation but this is not working due to bacteria living in TINY scratches on surfaces
What does the antimicrobial stewardship program involve? (acronym)
- STODNOE
- Survey
- Timeout
- Optimise therapy
- Diagnose
- New
- One health
- Education
What is the drug pipeline?
- Pre discovery
- Academia (Drug discovery and preclinical)
- Clinical trials (Phase I, II ,and III)
- Approval and market
Why is the drug pipeline a broken business model?
- Because the patent only lasts for two years
what is the rough pathway in the drug discovery pipeline?
- Infectious disease–> drug target? –> Target characterisation/hit candiadate search–> Hit candidate–> improve potency–> Lead optimisation–> Pre-clinical development
In the academia, reverse pharmacology section of the drug pipeline, what will an ideal drug target have?
- Be identified from fundamental research
- Inhibition or interference with its activity results in microbe death or a reduction in virulence of the disease model (enzyme will often be involved in the fundamental process required for survival)
- Good understanding of how the target functions in normal physiology
What is essential to have when starting a drug discovery project with a new drug target?
Sequence of the target o Amino acid for protein o Nucleotide for nucleic acid - In vitro production of target Activity assay o Robust, quick and cheap o Able to assess the activity of target the presence of drug-like compounds “hits”
What is desirable to have when starting a drug discovery project with a new drug target?
- Mechanism of action–> detailed knowledge of what the target does and how it achieves its function
- Structure of target
In terms of microbiology, what is a hit candidate?
- Active substance that has the desired microbial action on the microbe or in a disease model
- “hit” will be starting point to further develop or optimise active substance into drug
Which two places do you find the hits?
1) Start with the natural substrate and produce derivative 2) Screening libraries ( thousands to millions of candidates)
What is involved in starting with the natural substrate and producing a derivative to find hits?
- Making the natural substrate MORE drug like (i.e. so it still binds but can’t work)
What is involved in screening libraries to find hits?
- Purified natural products (pant derived, microbial metabolites, marine invertebrates)
- Purified chemical (Synthetic small molecules >300 Da stored for this purpose)
- Extracts (crude preparations of (often) natural substances)
- Fragments (small chemical entities <300 Da)
What are three methods to identify a hit in a library?
- High throughput screening (best option)
- Medium throughput screening
- In silico screening
What is high throughput screening?
10 000- 1 000 000s of compounds
- Robotic automated assays for large numbers of compounds (no humans)
- Target based or cell-based assays
- Expected hit rate= 1%
- 384, 1546, and 3456 well plates
What is medium throughput screening?
- 100s to 1,0000s of compounds.
- Semi-automated screening.
- Target-based or cell-based assays.
- Expected hit rate ~ 5 %.
- 96, 384, 1536 well plates
What is in silico screening?
- Generally, millions of compounds.
- Virtual screening of libraries.
What are the advantages of high thoughput screening?
- Automated (high speed + low running cost)
-Small volumes (less reagents = cheaper)
-Screen millions of compounds if desired
-Broad applicability (can do many different
types of assays)
What are the disadvantages of high throuhgput screening?
-Expensive infrastructure
- Can be difficult to optimize (translation of
complex assays from lab to a robot set-up
can be hard to achieve)
-Can have high rate of false positives
what are the advantages of medium throughput screening?
- Semi-automated (speed + low running cost)
- Cheaper set up (can be laboratory-based)
- Broader applicability (can do many different types of assays)
- Can get more data from single assay
- Less false positives
What are the disadvantages of medium throughput screening?
- Limited number of samples
- Larger volumes (more regents required)
What are the advantages of in silico screening?
- Cost
- Speed
- (Apparent) higher hit rate
What are the disadvantages of in silico screening?
- Requires drug target is known and extensively characterised (structure & mechanism)
- In reality, false positive ‘hits’ are very high
- Requires a very high level of understanding of protein chemistry
- Must be experimentally validated
What happens once a hit candidate has been identified?
- Identify the active ingredient/chemical composition of the “hit”
- In vitro production or supply of hit
- Re-test in a dose-response assay and confirm activity
What do you do when it is confirmed as a positive hit?
- Need the capacity to produce derivatives
- Screening assays for potency (likely the same as a hit search)
- Structure Activity Relationships (SAR)
- Structural information on how the hit works X ray crystallography of the drug interacting with the drug target
- Process goes until the potency is improved
What does SAR stand for?
- Structure Activity Relationship
When improving the potency of your drug what concentration do you want to go to?
- Want to go from mM –> pM potency
When does the transition from hit to lead optimisation occur?
- When the DESIRED potency has been reached (from in vivo validation in mice)
In the transition from hit to lead optimisation, what does the focus switch from?
- Switches from “having the most activity” to “Ensuring there are appropriate chemical properties for the hit candidate to be a drug in humans” –> Hit to lead
What is “hit to lead” known as?
- Hit candidate has the desired activity but a “lead” candidate has the desired activity AND drug like properties
What are 3 steps that occur in lead optimisation (3 aims) ?
- Solubility of the candidate
- ADMET (Adsorption- how well does it stick, Disposition - does it stay?, Metabolism, Excretion and Toxicity)
- Ensuring MINIMAL or NO “off target-effects”
- All of this must be achieved WITHOUT a drop in potency
What occurs in the pre-clinical development?
-`To determine the “safe-dose” for “first in man” studies and assess product safety profile –> MUST OCCUR BEFORE ANY HUMAN TESTING DONE
What 4 things in pre-clinical development is data obtained on?
1) Drug safety (safe and efficacious dose)
2) Feasibility (Can’t give someone a 1kg drug)
3) Pharmakodynamics (what drug does to body)
4) Pharmakokinetics (What the body does to the drug)
