Drug Design (III) Flashcards
What is the strongest type of interaction between molecules and what happens when a drug utilizes these interactions?
Covalent interactions
Make for very potent inhibitors as they are essentially irreversible (k2 ~ 0) and will stay bound until the receptor is recycled
Why haven’t researchers been developing more covalent inhibitors?
Risk of very strong side effects
What are the two types of covalent inhibitors? What are their mechanisms?
Mechanism-based/Suicide inhibitors and Targeted covalent inhibitors
Suicide inhibitors: Directly target a catalytic nucleophile within the active site of the enzyme
TCIs: targeting a non-catalytic nucleophile that is poorly conserved across protein family (more selective, fewer side effects)
Why are mild electrophiles used when designing a covalent inhibitor?
Won’t react with other nucleophiles
If drug is designed properly it will localise to the point where it will be very close to the nucleophile and not want to react with anything else
How can you measure protein interaction of your drugs? (and therefore infer safety)
Name two mehtods
Link reporter to ractive group and incubate with cell lysate
Then take your inhibitor and incubate with cell lysate, then again with reactive group
Compare SDS-PAGE of both trials and see which band(s) disappear
OR
Use click chemistry (alkyne-N2 reaction)
What are the 5 steps in developing a covalent inhibitor?
Computer-based drug design In vitro biology Chemistry Proteomics Clinical/Preclinical Pharmacology
What was found when reaction rate was plotted against inhibitor concentration?
It approaches an asymptote of k2
Why can’t IC50 be used for a covalent inhibitor?
The longer the drug is left with its target, the more likely it is to react (if you leave it alone long enough, even the weakest affinity will bind all drugs)
Why was Omeprazole so brilliant in its discovery?
It inhibited the last step of acid secretion (blocks acid release regardless of mechanism of action)
Prodrug that becomes active in acidic conditions, localises in acidic tissues (parietal cells) first
Why was esomeprazole a better enantiomer?
Better bioavailability (wasn’t metabolised by the body as much)
esomeprazole is a once-daily drug, yet it only lasts in the blood for a few hours. Why is this?
It irreversibly binds the proton pump
You only need to take another dose when the body replaces proton pumps
Why is Osimertinib a cautionary tale for Covalent inhibitors? How can drug designers avoid this?
It bound its target irreversibly but protein turnover took too long
You want to design a drug with a fine tuned reversible reaction so you can dial in the half life you want
What is a property of all metallo-enzymes
All incorporate a metal in their mechanism of action
