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BMS2052 MICRO > WEEK 9: DRUG TARGETS AND DRUG DESIGN > Flashcards

WEEK 9: DRUG TARGETS AND DRUG DESIGN Flashcards

1
Q

What are the urgent level hazards in terms of highly resistant pathogens?

A
  • clostridiodes difficile
  • CRE (Carbapenam-resistant Enterobacteriaece)
  • Drug resistant Neisseria gonorrhoeae
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2
Q

What is the concept of ‘One Health’?

A
  • 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
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3
Q

Are the same antibiotic classes used in humans and farm animals?

A
  • YES e.g. Chickens are given two antibiotics
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4
Q

What is the most deadly place for nosocomial infections?

A
  • ICUs!

- Rely heavily on sanitation but this is not working due to bacteria living in TINY scratches on surfaces

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5
Q

What does the antimicrobial stewardship program involve? (acronym)

A
  • STODNOE
  • Survey
  • Timeout
  • Optimise therapy
  • Diagnose
  • New
  • One health
  • Education
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6
Q

What is the drug pipeline?

A
  • Pre discovery
  • Academia (Drug discovery and preclinical)
  • Clinical trials (Phase I, II ,and III)
  • Approval and market
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7
Q

Why is the drug pipeline a broken business model?

A
  • Because the patent only lasts for two years
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8
Q

what is the rough pathway in the drug discovery pipeline?

A
  • Infectious disease–> drug target? –> Target characterisation/hit candiadate search–> Hit candidate–> improve potency–> Lead optimisation–> Pre-clinical development
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9
Q

In the academia, reverse pharmacology section of the drug pipeline, what will an ideal drug target have?

A
  • 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
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10
Q

What is essential to have when starting a drug discovery project with a new drug target?

A 
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”
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11
Q

What is desirable to have when starting a drug discovery project with a new drug target?

A
  • Mechanism of action–> detailed knowledge of what the target does and how it achieves its function
  • Structure of target
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12
Q

In terms of microbiology, what is a hit candidate?

A
  • 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
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13
Q

Which two places do you find the hits?

A

1) Start with the natural substrate and produce derivative 2) Screening libraries ( thousands to millions of candidates)

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14
Q

What is involved in starting with the natural substrate and producing a derivative to find hits?

A
  • Making the natural substrate MORE drug like (i.e. so it still binds but can’t work)
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15
Q

What is involved in screening libraries to find hits?

A
  • 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)
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16
Q

What are three methods to identify a hit in a library?

A
  • High throughput screening (best option)
  • Medium throughput screening
  • In silico screening
17
Q

What is high throughput screening?

A

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
18
Q

What is medium throughput screening?

A
  • 100s to 1,0000s of compounds.
  • Semi-automated screening.
  • Target-based or cell-based assays.
  • Expected hit rate ~ 5 %.
  • 96, 384, 1536 well plates
19
Q

What is in silico screening?

A
  • Generally, millions of compounds.

- Virtual screening of libraries.

20
Q

What are the advantages of high thoughput screening?

A
  • 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)
21
Q

What are the disadvantages of high throuhgput screening?

A

-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

22
Q

what are the advantages of medium throughput screening?

A
  • 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
23
Q

What are the disadvantages of medium throughput screening?

A
  • Limited number of samples

- Larger volumes (more regents required)

24
Q

What are the advantages of in silico screening?

A
  • Cost
  • Speed
  • (Apparent) higher hit rate
25
Q

What are the disadvantages of in silico screening?

A
  • 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
26
Q

What happens once a hit candidate has been identified?

A
  • 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
27
Q

What do you do when it is confirmed as a positive hit?

A
  • 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
28
Q

What does SAR stand for?

A
  • Structure Activity Relationship
29
Q

When improving the potency of your drug what concentration do you want to go to?

A
  • Want to go from mM –> pM potency
30
Q

When does the transition from hit to lead optimisation occur?

A
  • When the DESIRED potency has been reached (from in vivo validation in mice)
31
Q

In the transition from hit to lead optimisation, what does the focus switch from?

A
  • 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
32
Q

What is “hit to lead” known as?

A
  • Hit candidate has the desired activity but a “lead” candidate has the desired activity AND drug like properties
33
Q

What are 3 steps that occur in lead optimisation (3 aims) ?

A
  1. Solubility of the candidate
  2. ADMET (Adsorption- how well does it stick, Disposition - does it stay?, Metabolism, Excretion and Toxicity)
  3. Ensuring MINIMAL or NO “off target-effects”
    - All of this must be achieved WITHOUT a drop in potency
34
Q

What occurs in the pre-clinical development?

A

-`To determine the “safe-dose” for “first in man” studies and assess product safety profile –> MUST OCCUR BEFORE ANY HUMAN TESTING DONE

35
Q

What 4 things in pre-clinical development is data obtained on?

A

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)

BMS2052 MICRO (10 decks)

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