Topic 4: drug discovery and sources of novel bioactivities

Question 1

Assays in TDD and PDD

Answer 1

TDD:

Binding assays: i.e. Surface plasma resonance, radioligand displacement assay

Functional or biochemical assays: Kinase, second messenger mobilization

PDD:

• Bioassays are models of the disease and measuring disease-modifying properties of the screening compounds. They can also be used to validate hits from target based assays
• In vitro: cells and multicellular tissues that reflect disease hall-marks
• In vivo: use of animal models (typically transgenic)

Question 2

TDD pros and cons

Answer 2

Pros:

• Rational MOA
• Can use siRNA to probe MOA and validate chemistry
• Aid compound design through determination of structure

Cons:

• Resource intensive
• High failure rate ( 99%)
• Reliant on established druggability

Question 3

PDD pros and cons

Answer 3

Pros:

• Direct screening and direct validation
• Target must be druggable
• Can identify novel MOA

Cons:

• Hard to obtain suitably diverse libraries
• Suitably robust phenotypic assays are hard to generate
• MOA unknown difficult to predict disease relevance and safety

Question 4

TDD libraries

Answer 4

bias on favourable PK

Question 5

PDD libraries

Answer 5

bias of potency and selectivity

Question 6

Diversity considerations and LE

Answer 6

• Diversity within aa drug like space is enormous and difficult to populate with fully potent compounds for each possible target
• Easier to populate this space with small ligand efficient compounds (fewer binding motifs and lower N)

Question 7

evaluating hits

Answer 7

LE (affinity for MW): 1.4 (-log Ki/N) > 0.3
LipE (affinity a logP) :-lok Ki- log P >4.5
LELP: LogP/Le < 10 (0-7.5)