Drug Discovery and Development

Question 1

Recall the steps of drug discovery and development.

Answer 1

Question 2

What is considered during the therapeutic concept?

Answer 2

• Choose a disease/therapeutic area
  
  • commercially driven choice
    
    • unmet medical need
    • significant market
    • market share opportunity

Question 3

What is being considered during target identification?

Answer 3

• Target identification
  
  • Known biology of disease
  • Result of target finding
    
    • Based on endogenous or plant-derived ligand with known activity or “omics-based” search
  • Differential expression
    
    • mRNA/protein
    • polymorphism

Question 4

What is done during target validation?

Answer 4

• Target validation is the process by which the predicted molecular target – for example protein or nucleic acid – of a small molecule is verified.
  
  • Transgenic -/- or overexpression
  • Natural variants
  • Induced mutations – nitroso-urea
  • CRISPR Cas9
  • siRNA on cells

Question 5

Differ between target-based and phenotype screening

Answer 5

• Phenotypic screening –searching for “hits” based on effects in cells and organisms
• Target-based screening -searching for hits based on direct interaction of chemical with target protein

Question 6

What is done during lead identification?

Answer 6

This is the process whereby ‚”Hits” from screening are transformed into “Leads” that can be then used for “Lead Optimisation”

• From chemical to lead compound
  
  • Potent and selective
  • Lipinski’s rule of 5 (features of chemistry eg <500 mw)
  • Aqueous solubility (for oral absorption)
  • Permeability through epithelial cell layers
  • Oral availability in experimental animals
  • Metabolic stability in liver extract
  • Sufficient plasma T1/2 to gain effect in vivo

Question 7

What is a lead?

Answer 7

A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target

Question 8

What is done during lead optimization?

Answer 8

• From lead compound to drug candidate
• These features are on the wish-list
• Aqueous solubility (for formulation)
• No reactive metabolites
• No major active metabolites
• Not metabolised by polymorphic enzymes
• T1/2 to allow “reasonable” dose interval