Covalent inhibitors

12 important questions on Covalent inhibitors

What are the classes of drugs?

- Therapeutics
- Diagnostics
- Indication area
- chemicals
- biologicals
- target classification

What kind of therapeutic areas do we have?

- cancer (e.g. Taxol): inhibitrs cell division by binding and stabilizing microtubules
- inflammation (e.g. aspirin and ibuprofen)
- infection (imipenem): kills both gram + and gram - bacteria. by inhibiting cell wall synthesis.

What are covalent inhibitors?

They form a reversible or irreversible bond to the receptor.
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What are some historical examples of approved covalent drugs?

- aspirin
- Penicilin
- cephalosporin C
- Fosfomycin
- Lansoprazole
- omeprazole
- clopidogrel

What biological amino acids are nucleophiles?

cysteine (is the best)
lysine
Serine
Threonine
Tyrosine

What kind of classes of electrophiles in small molecules do we have?

- halides
- acrylamides
- subst. acrylamide
- vinyl sulfones
- beta lactame
- beta lactone
- epoxide
- nitrile
- disufite

What are examples of reversible covalent drugs?

- Bortezomib
- Dimethyl fumarate
- Telprevir, Boceprevir
- Rivastigmine

What are examples of irreversible covalent drugs?

- Finasteride
- Neratinib

What are side effects of aspirin?

- stomach ulcers
- stomach bleeding
- worsening asthma
It is due to an irreversible inactivation of COX

What is a problem with penicillin?

Resistence due to an upregulation of beta-lactamases that can deactivate beta lactam antibiotics.

What are benefits of covalent inhibitors?

- there is a prolonged duration of a drug action on the target.
- 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?

- fast irreversible binding to target
- 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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