11.08.2021 11.30
Medchem I&II
Q: Tell me about Hight throughput screening. How it is made and what it is used for.
A: It’s a method to find an appropriate lead for your target. You screen for millions of molecules. You have two different approaches: rationally and randomly. In the rationally you restrict your libraires whereas in the randomly you scan all the molecules.
Q: But how specific works the HTS?
A: I had no idea how it works specific, I only said: you have wells where you put first your target, then you put an agonist which can be fluorescent marked and then in every well you put a different molecule. When the right one binds to the target you have a signal (not really sure what he answered, he changed question…)
Q: You said there are millions of molecules where are the from?
A: …Database
Q: Yes, but they cost very much so where are they from?
A: …
Q: From natural product! What is the advantage and the disadvantage with natural product?
A: disadvantage: natural products are often very complicated structure so you have to simplify. Advantages: you can target also molecule that will not be drougable with normal molecules.
Q: True but normally you will not perform a HTS for molecules which are not drougable.
A: ...ok.
Q: Tell me what do you know about cholinergic receptor?
A: There are two different types, nicotinic is ion channel, muscarinic is GPCR.
Q: Acetylcholine will be hydrolyzed by acetylcholinesterase. Then he showed me the structure of acetylcholine in the acetylcholinesterase binding pocket. Where the esterase cleaves? And what is the function of serine?
A: it cleaves the ester group and serine make a nucleophilic attack.
Q: He showed me the structure of physostigmine and other acetylcholinesterase inhibitors.
Q: Can you draw the mechanism of inhibition?
A: I draw the mechanism (slide 41).
Q: What is the advantage for the structure of neostigmine and pyridostigmine?
A: Since the nitrogen is protonated, they will not pass the BBB and reduce side effect in the CNS:
Q: True, but also physostigmine has two nitrogen atoms.
A: I tried with maybe they are cleaved. (false 😉)
Q: The answer is that in physostigmine the nitrogen are only temporarily charged.
Q: Then he showed me a structure with the name (Palbociclib). I know you have never seen this structure. What can be?
A: It was a protein kinase since there was the typical aminopyrimidine group.
Q: What makes the aminopyrimidine group.?
A: It binds in the binding site where normally ATP can bind in kinases.
Q: It is possible that this molecule is a covalent inhibitor? and if yes which part of the molecule is the covalent inhibitor?
A: I had no idea…I tried with some group that seem to be reactive (like carbonyl, …)… sorry but I really didn’t understand his answer.
Q: About the group on the right (is a six member ring with N and NH), why the chemists add this group very often to the molecules?
A: Maybe the nitrogen atoms are reactive and can make some interactions in the active site.
Q: No, it’s not about pharmacodynamics.
A: mmm also for the pharmakokinetik.
Q: yes, because the nitrogen can be protonated an so it’s better soluble in water.
A: yes but so it pass the membrane difficult
Q: he answered it’s always a balance or something like that