Siegel

Question 1

Pros for Covalent Drugs

Answer 1

• High biochemical efficiency; may translate to a lower dose and reduce off target effects
• Non-equilibrium binding can help overcome competing endogenous substrates that bind to the same target
• Covalent binding can mitigate the development of drug resistance resulting from mutations in the active site
• Can potentially address targets with shallow binding sites

Question 2

Cons for Covalent Drugs

Answer 2

• Potential risks for idiosyncratic toxicity and/or immune response-mediated drug hyper-sensitivity
• Hyper-reactive warheads can lead to drug-induced toxicity
• Not suitable for mechanisms requiring short residence times / partial inhibition
• Little advantage for biological targets that are rapidly turned over by protein synthesis

Question 3

Prodrug + why use one

Answer 3

• A prodrug is an inactive substance that is activated in our bodies
• Can use a prodrug to change the selectivity of drug interaction with things that aren’t its intended target. Can reduce adverse/unintended effects.
• Can be used to improve drug delivery or pharmacokinetics, to decrease toxicity, or to target the drug to specific cells or tissues.

Question 4

Chirality

Answer 4

• One enantiomer may be useful/effective in a treatment, while another may be inactive/toxic