L27 + 28 - The Modern Drug Discovery Pipeline / Design Techniques

Question 1

Why do drugs fail getting to market?

Answer 1

Wrong molecule made
- efficacy
- safety
- commercial

Question 2

How is disease state assessed by?

Answer 2

Taking clinical samples from patients or using established models

Question 3

What methods are used to identify the target?

Answer 3

• genomic
• proteomic
• genetic association

Question 4

What do genomic methods seek to identify?

Answer 4

Differential expression of mRNA in the disease state

Question 5

What is the mRNA used for in target identification?

Answer 5

• make protein
• changes to levels of mRNA can lead to changes in the amount of protein present in the disease state

Question 6

What do proteomic methods seek to identify?

Answer 6

• differential expression of proteins in the disease state
• functional chanfes to proteins

Question 7

What is high throughput screening?

Answer 7

Technique where large numebrs of chemical compounds (libraries) are rapidlt tested for activity against our chosen target

Question 8

What is the advantage of high throughput screening?

Answer 8

Highly automated

Question 9

What are considerations of high throughput screening?

Answer 9

• screening is random
• active compounds usually provide us with a starting point

Question 10

What is virtual screening?

Answer 10

Computational methods to predict:
- how a compound will bind to a protein
- what compound might bind to a protein
- how strongly a compound might bind to a protein

Question 11

What are advantages of virtual screening?

Answer 11

Don’t need to physically make the compounds

Question 12

What are disadvantages of virtual screening?

Answer 12

Need to know exact position in 3D space of all atoms in protein

Question 13

What does protein crystallography reveal?

Answer 13

3D structure of protein and bound compounds

Question 14

What does visualisation of complex proteins and potential drugs help scientists with?

Answer 14

Understand mechanism of action of the drug and to inprove the design of a drug

Question 15

What does visualition of these complex proteins and potential durgs use?

Answer 15

Computational ball and stick model of atoms and bonds, as well as surfaces

Question 16

What are the steps in virtual screening?

Answer 16

• put compound in approximate area where binding occurs
• generic algorithm encodes orientation of compound and rotatable bonds
• optimise binding to protein
  = provides rational screening method to identify scaffold

Question 17

How do you optimise binding to protein?

Answer 17

• minimise energy
• hydrogen bonding
• hydrophobic interactions

Question 18

What is combinatorial chemistry?

Answer 18

Techniques for producing large numbers of compounds
- in a short period of time
- using defined reaction routes and a large variety of starting materials and reagents

Question 19

What is an example of combinatorial chemistry?

Answer 19

Multi-component reaction
- quickly generates a library of 160,000 compounds with dif R1, R2, R3, and R4

Question 20

What are requirements for combinatorial chemistry?

Answer 20

• highly efficient chemistry
• limited work-up, isolation and purification
• rapid throughput

Question 21

What are advantages if combinatorial chemistry is achieved?

Answer 21

• vast increases in productivity
• chemistry bottlenecks in drug discovery process can be prevented
• companies can patent sooner
• cost savings and increased time for revenue generation

Question 22

What does molecular modeling use?

Answer 22

Similar methods to virtual screening
- carried out after we already have out lead compound

Question 23

What is molecular modeling used to try to optimise?

Answer 23

Pharmacophores for improved binding (efficacy)

Question 24

How do you optimise pharmacophore binding to the protein?

Answer 24

• minimise energy
• hydrogen bonding
• hydrophobic interactions

Question 25

What do ADME techniques help model?

Answer 25

How the drug will likely act in the. Body

Question 26

What can these methods be (for ADME)?

Answer 26

experimental
- using cellular tissue, or in silico, using computational models

Question 27

What are in vitro ADME models based around?

Answer 27

Real tissue samples
- have similar properties to those in the body
= cuts down on animal tests (pre-screen)
- enables discovery of data on many more compounds

Question 28

What does the caco-2 permeability assay help to understand?

Answer 28

Suitability of a compound for oral dosing
- predicting human intestinal permeability and drug efflux

Question 29

How does the cac0-2 permeability assay investigate the intestinal permeability?

Answer 29

By measuring the rate of transport of a compound across the caco-2 cell line

Question 30

What is the caco-2 cell line derived from?

Answer 30

Human colon carcinoma
- resemble intestinal epithelial cells (formation of polarised monolayer, well-defined brush border on the apical surface and intercellular junctions)

Question 31

What can computational methods can predict compound properties?

Answer 31

• logP, lipophilicity measure
• solubility
• permeability
• CyP450 metabolism