Medicinal chemistry and drug discovery

Question 1

What information to use to find a new molecule?

Answer 1

Use chemical libraries (stem cell signaling, epigenetics, DNA encoded libraries, etc.)

Question 2

When a hit is found, what are important aspects to check in “lead optimization”?

Answer 2

• Identity: positive
• Purity: >90%
• Stability: >80%, 6h
• Metabolic stability
• Permeability
...

Question 3

What is a “structure based design” and what does it study?

Answer 3

• Study the receptor-ligand interactions
• Propose new ligands
• Dock new ligands
• Evaluate the new ligands
• Synthesize the most promising and interesting new ligands

Question 4

What are the criteria that a candidate drug needs to fill (in lead optimization)?

Answer 4

• Efficacy
• Safety
• Deliverable
• Chemistry amenable for scale-up
• Intellectual property rights secured

Question 5

What is an ADMET assays?

Answer 5

1. Administration/Absorption: how to get the drug into the body
2. Distribution: where in the body the drug goes
3. Metabolism: break down of the drug by the body
4. Excretion/Elimination: how to get the drug out of the body
5. Toxicology: drug may have toxic effects on the body

Question 6

What is a xenobiotic?

Answer 6

A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it

Question 7

What does the phase 1 metabolic reactions of an administrated durg refer to?

Answer 7

A metabolite which is formed as a result of a direct change on the administered drug

Question 8

What does the phase 2 metabolic reactions of an administrated durg refer to?

Answer 8

A new metabolite formed as a result of the addition of an endogenous component to the administered drug and/or to the first phase metabolites

Question 9

What is the difference between Drugs and Probes?

Answer 9

Drugs: must be safe and effective

• may have undefined modes of action
• intellectual restrictions/limited availability
• must have human bioavailability
• high bar for physicochemical and pharmaceutic properties

Probes: ask a specific biological question

• defined modes of action is required
• need selectivity
• freely available (physical compound and activity data)
• drug-like properties

Question 10

What is an affinity-based chemical proteomics “pull-down”?

Answer 10

1. Immobilised probes are mixed with cell lysates
2. Wash away unbound proteins
3. Evaluate target proteins
4. Analyze