12. Molecular Drug Targets and Design

Question 1

What is an early medicine?

Answer 1

• Derived mainly from plants
• Discovered by trail and error experimentation in humans
• All ancient civilisations made discoveries in this field- especially Chinese
• Examples include: quinine for malaria and mercury for syphilis

Question 2

How did modern drug discovery begin?

Answer 2

• Began in early work on Treponema Syphillis in which Paul Ehrlich systematically synthesised chemical variants that cured mice and men of Syphillis (not trial and error)
• It was discovered that a fungal mold could kill Staphylococcus leading to synthesis of penicillin and wide antbiotic generation

Question 3

What is drug design?

Answer 3

• The inventive process of finding new medications

Question 4

What is antimicrobial resistance?

Answer 4

• Many bacteria, fungi and parasites evolve resistance to drugs used to combat them
• Currently due to widespread antibiotic use the rate at which AMR is occurring is greater than the rate at which we are developing antimicrobial drugs

Question 5

What is the drug pipeline?

Answer 5

• It takes 10-15 years to get a drug to market
• Phases:
  1. Pre-discovery
  2. Discovery
  3. Pre-clinical trials
  4. Clinical trials

Question 6

What is forward pharmacology?

Answer 6

• When you have a target disease and you are looking for a drug to treat it
• Involves looking for a hit candidate (an active substance that has the desired anti-microbial action on microbe or disease model)
• You make derivatives of hit candidate trying to make improvement to potency by screening for activity
• Then it undergoes lead optimisation to see if the compound is drug-like whilst maintaining potency
• Enter the cycle again
• If successful enter pre-clinical development

Question 7

What is reverse pharmacology?

Answer 7

• Identifying a drug target first e.g. a protein or nucleic acid required for survival in pathogen
• Undergoes target characterisation: understanding the biology of the drug target (sequencing, assays
• Only then do they look for a hit candidate

Question 8

What are the essential features of a new drug target?

- What are desirable features?

Answer 8

Essential: 
- Sequence of target
In vitro production of target
- In vitro production of target
- Activity assay 

Desirable:

• Mechanism of action
• Structure of target

Question 9

What is the difference between a “hit” and a “lead” candidate?

Answer 9

• A hit candidate is an active substance that has desired anti-microbial action on microbe or in disease model- aim is to develop it into a lead candidate
• A lead candidate has pharmalogical of biological function likely to be therapeutically useful

Question 10

How are hit candidates found?

Answer 10

1. Starting with a natural substance and producing a derivative to make the substance more drug-like
2. Screening libraries:
   - libraries filled with thousands of possible candidates that are identified through high-throughput screening, low-throughput screening and in silico screening

Question 11

How do you screen for hits in a library?

Answer 11

1. High-throughput screening:
   - robotic, automated assays for large number of compounds
   - expensive infrastructure and false positives
2. Medium throughput screening:
   - semi-automated screening
   - uses large welled plates to conduct assays
   - cheaper set up and less false positives than high-throughput
   - but limited to a number of samples and requires more reagents (running costs)
3. In silico (computational) screening:
   - Virtually screening libraries
   - Very cheap and quick
   - Assumes that drug target is known and characterised
   - Only works for reverse pharmacology
   - many false positives
   - needs to be experimentally validated

Question 12

What occurs once a hit candidate has been identified?

Answer 12

• Identify the active substance/chemical composition of a hit
• The hit must be produced in vitro or have an available
• Re-test hit in dose-response assay (more hit should lead to greater killing of microbe)

Question 13

What is forward genetics vs reverse genetics?

Answer 13

Forward genetics: screens for hit first

Reverse genetics: identifies potential drug target then finds a hit

Question 14

What do you do with a hit candidate?

Answer 14

• With the hit you screen for potency and structural-activity relationships
• Generate derivatives

Question 15

What is a lead-candidate?

Answer 15

• Has pharmacological or biological activity that is likely to be therapeutically useful (drug-like properties)

Question 16

What is hit to lead optimisation?

Answer 16

• Once the hit candidate has been optomised (potency sufficient) you perform in vivo validation
• Once this is confirmed it enters the derivative testing cycle once more to find candidate with the best potency
• The focus then switches from the candidate being the most potent to the most drug like (hit to lead search)
• Focus of hit-to-lead optomisation is:
  1. Solubility of candidate
  2. ADMET
  3. Ensuring minimal/no off target effects
• all without a loss of potency
• you enter a similar interative cycle

Question 17

What is pre-clinical development?

Answer 17

• Aim is to determine safe dose for human in first in man studies and assess product safety