How Drugs Bind to their Targets 1

Question 1

How can ACh bind to multiple targets?

Answer 1

• Acetylcholine (ACh) can adopt many shapes and bonding patterns
• Pharmacophores (shape and chemical properties) required for optimal activation can vary for different receptors
• Selective agonists (or antagonists) may mimic one ACh conformation

Question 2

Why is muscarine unable to bind to nicotinic ACh Receptors?

Answer 2

Muscarine ring restricts the number of conformations. Nicotine is also restricted by a ring and can only bind to nicotinic receptors.

Question 3

What are the features of the Ligand Binding Site of mAChR?

Answer 3

• Ionic bonding at deep end of binding pocket
• H-bonds can orientate ligand
• Open-end of the binding site allows for longer chain

Question 4

What is Bioisosteric Replacement?

Answer 4

Bioisosteric replacement is the replacement of a binding group in a drug with another group
- Why? Improve potency or selectivity