Covalent inhibitors
12 important questions on Covalent inhibitors
What are the classes of drugs?
- Diagnostics
- Indication area
- chemicals
- biologicals
- target classification
What kind of therapeutic areas do we have?
- inflammation (e.g. aspirin and ibuprofen)
- infection (imipenem): kills both gram + and gram - bacteria. by inhibiting cell wall synthesis.
What are covalent inhibitors?
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What are some historical examples of approved covalent drugs?
- Penicilin
- cephalosporin C
- Fosfomycin
- Lansoprazole
- omeprazole
- clopidogrel
What biological amino acids are nucleophiles?
lysine
Serine
Threonine
Tyrosine
What kind of classes of electrophiles in small molecules do we have?
- acrylamides
- subst. acrylamide
- vinyl sulfones
- beta lactame
- beta lactone
- epoxide
- nitrile
- disufite
What are examples of reversible covalent drugs?
- Dimethyl fumarate
- Telprevir, Boceprevir
- Rivastigmine
What are examples of irreversible covalent drugs?
- Neratinib
What are side effects of aspirin?
- stomach bleeding
- worsening asthma
It is due to an irreversible inactivation of COX
What is a problem with penicillin?
What are benefits of covalent inhibitors?
- Target inhibition persists after the drug has been cleared.
- less frequent dosing and lower drug doses.
What is the profile for a ideal covalent inhibitor?
- target should have a long t1/2 in vivo.
-rapid clearance to minimize off-target interactions (both covalent and non-covalent)
- reduce non-mechanism-based toxicity
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