drug design

Question 1

drug discovery pipeline

Answer 1

• find target gene/protein/molecule
• discover hit
• hit to lead
• optimise lead
• clinical trials
• sales

Question 2

hit

Answer 2

• small molecule with an effect identified biologically/computationally
  
  • high throughout screening
• either purchased or belonging to a chemical library
  
  • no patent possibility if purchased

Question 3

lead

Answer 3

• chemically modified hit with enhanced effects and better ADMET
• ideally IC50 = 1nM (μM min)
• improved delivery and decreased toxicity

Question 4

lead optimisation

Answer 4

• potency (<1nM)
• selectivity (1000 fold against related receptor)
  
  • prevent effects on homologues
• solubility (<1mg/ml)
• ADMET
• safe and tolerable in animals
• efficacy in animals

Question 5

IC50

Answer 5

• half maximal inhibitory concentration
• concentration that has 50% inhibiton of the target
• measure of efficacy

Question 6

clinical trials

Answer 6

1. establish safe dose, side effects, absorption
2. establish efficacy and side effects
   
   • confirmation of 1
3. prove efficacy
   
   • compare to other treatments
   • random double blind
   • against placebo or alternative
4. regulation/monitoring phase

Question 7

targets of drug design

Answer 7

• identify macromolecular target
• find IC50
• 1000 fold improvement in IC50 to 1nM

Question 8

ADMET

Answer 8

• absorption
• distribution
  
  • target vs off target
• metabolism
  
  • conversion to metabolites
  • prodrugs/bioactivation
  • pharmacokinetics and pharmacodynamics
• excretion
  
  • aim to minimise (take drug less often)
• toxicology
  
  • acute and chronic
  • 2 species before humans

Question 9

lipinskis rule of 5

Answer 9

• MW ≤500
• lipophily ClogP ≤5
• ≤5 H bond donors
• ≤10 H bond acceptors
• distinguishes drug like molecules from non-drug like

Question 10

extension of lipinskis rule of 5

Answer 10

• number of atoms between 20 and 70
• at least one OH (except psychoactive substances)
• <8 rotatable bonds
  
  • reduce unfavourable entropy of free molecule becoming fixed
• many drugs break these

Question 11

high throughput screening

Answer 11

• series of small molecules form library plates and tested robotically
• 10⁵-10⁶ compounds at a time
• expensive
• up to 1 million moelcules
  
  • but 1 billion possible drugs predicted

Question 12

computer based drug design

Answer 12

• involves ligands and receptors
  
  • ligand = small molecule (sometimes macromolecule)
  • receptor = macromolecule/protein/nucleic acid
• type of modelling depends on how much you know about each
• major aim is scaffold hopping
• based on pharmocophore

Question 13

types of computer-based modelling for drug design

Answer 13

• know activities of set of ligands but not receptor
  
  • often with membrane proteins
• know receptor structure but not active ligand structure
• know structure of receptor-ligand complex

Question 14

scaffold hopping

Answer 14

• find new molecule structurally different to something that already exists
• can patent
• improve efficacy and reduce side effects

Question 15

pharmacophore

Answer 15

• set of molecular features arranged in their relative spatial orientation repsonsible for that molecule’s interactions
  
  • H bond acceptors/donors
  • charged groups
  • hydrophobic regions
  • aromatic rings
• what the target receptor recognises
• developed by ligand scout program

Question 16

rationale behind pharmocophore

Answer 16

• bioisosterism
  
  • certain functional groups have similar properties
• distinct functional groups can be exchanged while maintaining biological activity
• useful in identifying structures with desired acitivity in unexplored chemical series
• scaffold hopping
• pharmacophore can’t be patented

Question 17

advantages of pharmacophore

Answer 17

• add more geometric features
  
  • centroids, planes, angles
  • excluded volumes (not occuppied by ligand)
    
    • limit searching options
  • specified distances or ranges (increased flexibility)
• underpins basis of computer-aided drug design methods