Drug discovery lecture 5

What are the 3 Stages of drug discovery?

Discovery

Development

Clinical Use (trials)

What are some early-stage drug discovery strategies

•(Fragment-based) combinatorial chemistry

•Phenotypic screening

•Virtual screening

•Rational drug design

What are the stages of —(Fragment-based) combinatorial chemistry?

Step 1: synthesis of building blocks bearing connecting groups X and Y

Step 2: Generation of combinatorial libraries by independent synthesis and purification

Step 3: Lead identification by high-throughput screening, testing each compound for activity

What is phenotypic screening?

Test of small molecules that alter a phenotype

What is screening? Definition:

testing extracts against cell lines derived from a diverse array of human tumors

What is virtual screening

Computer-based docking of a diverse family of small molecules with homology models of the biological target.

What is Rational Drug Design

•Identification of the natural ligand of the biological target

•Mapping of molecular interactions between the ligand and the target

•Substitution of structural features of the natural ligand to create agonist/antagonist

what is rational drug design based on

druggabilty and target validation

how is target validation important in rational drug design

for the

1. target involved in biomedical cascade of disease

2. target responsive to small molecule treatment

why is virtual screening preffered over phenotypic screening

virtual is cheaper and faster

Select which one of the following options identifies the 2 main properties of druggable biological macromolecules [1 mark]

a. The macromolecule must be involved in a disease state and must respond to treatment with the drug

b.The macromolecule must not be involved in a disease state and must respond to treatment with the drug

c.The macromolecule must be involved in a disease state and must not respond to treatment with the drug

d.The drug molecule must bind to the macromolecule and inhibit its activity

e.None of the above

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State a typical characteristic of phenotypic screening and provide an example of successful phenotypic screening.

Phenotypic screening is typically very expensive [1 mark].

The discovery of taxol is a successful example of phenotypic screening [1 mark].