Drug discovery (3)

Question 1

Drug optimisation

Answer 1

• Drugs need to have a wide range of desirable properties to be effective
• High receptor affinity is necessary but not sefficient
• Drug discovery is increasingly multi-objective optimisation

Question 2

Affinity vs PK profile

Answer 2

• Affinity
  
  • Potency, selectivity, side effects
• PK profile
  
  • Intestinal absorption
  • Cell permeability
  • Protein binding
  • Metabolic degradation
  • Clearance
  • Drug deposition
• Tug of war- increase affinity, change PK- improve PK lower affinity

Question 3

Affinity vs PK profile

Intrinsic activity vs Global properties

Answer 3

• Intrinsic activity
  
  • Pharmacophore complementary
  • Conformational flexibility
  • Protein interactions
  • How drugs act at a receptor
• Global Properties
  
  • Membrane interactions
  • Acidity / Basicity
  • LogP, LogD etc
  • How drug reaches receptor

Answer 4

• Desarable properties are often in tension
• Trade-off between affinity, selectivity & PK properties
• As one increases, the other decrease
• Balance between local and global properties

Question 5

Drug optimisation has 2 phases

Answer 5

• Hit-to-lead
  
  • Rapid using fast technique (parallel synthesis)
• Full MedChem project
  
  • Slower (Single synthesis)
    *

Answer 6

• SBDD uses knowledge of the receptor structure to guide the design of new compounds able to exploit unfulfilled interactions and shape complementarity
• LBDD uses knowledge of ligand structure with or without knowledge of the receptor to create models based on structural properties able to discriminate good compounds from bad

Question 7

Fragment-based approaches

Answer 7

• Start with a small fragment (bind small molecule to target protein) =>
• Use Biophysical technique X-ray / NMR/ ITC (gives us a detail picture of how are molecule binds to protein) =>
• To grow molecule improving affinity and PK profile

Question 8

Fragment selection

Answer 8

• Rule of three- fragments are much smaller this means the rules are tighter
  
  • Molecular weight is <300
  • N^o H-bond donors is <3
  • N^o H-bond acceptors <3
  • and ClogP is <3
  • Ideally NROT <3 and PSA <60

Question 9

Structure-based drug design

Answer 9

• Computational
  
  • SB-APD (Automated protein docking)
  • Quantum Mechanics
  • Molecular dynamics & Stimulated annealing
• Experimental
  
  • X-ray crystallography
  • Multi-dimensional NMR
  • Neutron diffraction

Question 10

Important features- for drugs

Answer 10

• Fill hydrophobic cavities
• Look to pick-up favourable interactions
• Steric complementarity
• Avoid clashes with proteins
• Other features affect overall physical characteristics (LogP etc) that alter ADMET and PK properties

Question 12

Drug repositioning- Viagra

Answer 12

• Sildenafil was synthesized at Pfizer’s sandwich research site
• Its intended for use in HTN and angina pectoris
• Phase I trials indicated poor efficacy in angina, but identified an interesting side effect

Question 13

Aspirin

Answer 13

• Aspirin is possibly the most widely used medications globally: ~40,000 tonnes prescribed annually
• Analgesic for minor pain
• Antipyretic to reduce fever
• Anti-inflammatory medication
• Anti-coagulants
• Aspirin may help preventing certain cancers: i.e. colorectal cancer

Question 14

drug repositioning- positive aspects

Answer 14

• Compounds already passed through clinical trials
• Fully evaluated from a safety perspective
• Need to demonstrate efficacy and/or added-value
• Potential saviour for Pharma R&D
• Many examples of successful repositioning are known
• Repositioning rate now exceeds the rate of drug discovery
• Faster and more efficient as some of the work is already done

Question 15

Drug repositioning steps

Answer 15