MedChem I & II
12.08.2021


NO GUARANTEE OF CORRECT ANSWERS

Mr. Hall is very relaxed, his goal is to have a discussion with you. Though if you drift too far from what he wants to hear he will tell you immediately. It's also rather based on understanding concepts than learning drugs by heart.

Hall: What does the term drug drug interaction say to you?
Talked about metabolism, enzyme family P450 and CYPs, especially CYP3A4

Hall: Why is it important?
side effects, toxicity, accumulation of substrates, danger for the patient

“he showed me a table of common substrates, inducers and inhibitors of CYPs”
Hall: What useful information can be seen in this table? Could you explain with an example.
Talked about Warfarin as a substrate and how the enzyme is inhibited by Cimetidine, leading to slow conversion of Warfarin and accumulation, possibly dangerous bc of limit of therapeutic window / toxicity

Hall: Cimetidine is on this table, what does Cimetidine bind?
I didn’t know, he said it was an H2 antagonist

Hall: What does an inhibitor do? Explain with the example of Cimetidine
Talked about how in competes with the natural ligand for binding but doesn’t lead to an induced fit and therefore there’s no cell signal.

Hall: What is the natural ligand of the H2-receptor? Can you draw me the structure?
Histamine

Hall: What effect do H2- inhibitors have in human?
Used for treatment against peptic ulcers as they inhibit gastric acid secretion in the stomach

Hall:*he showed me a picture of the slide with the HCl secretion inhibition, with H2, M3 and gastrin receptors*
Hall: Why is the proton pump a better target than the H2-receptor?
It is a more downstream signal, I said it has fewer side effects which he only partly agreed on. He talked about how there is no influence of M3, gastrin or H2 receptors if the proton pum is inhibited directly.

Hall: *showed a picture of PPIs*
I didn’t recognize them, although we just talked 5min about them. He said they are PPIs.

Hall: *picked one of the PPIs* This molecule is chiral. Where is it’s chiral center?
I didn’t find one, he said it was a trick question as the sulfur atom is chiral, having one double bond to the oxygen, on free electron pair and to more covalent bonds.

Hall: Why are racemic mixtures not desired?
I said most of the times only one of them is active.
Hall: Why?
*short (intense) silence*
Hall: because they have different 3D structures. DO you think this molecule has a big difference between the two enantiomers?
I said no because it’s rather small.
Hall: Yes, because either the oxygen point upwards or downwards, which does not make that big of a difference compared to larger drugs.

Hall: Histamine receptors are GPCRs. *He showed me the slide with the three different GPCRs and what their effect is*
Hall: What does this table tell you? Why is this useful for us?
Talked about different effects of different GPCR subtypes. He didn’t really like that answer.

Hall: There is a difference in H2 and H1 receptor, they signal differently.
Hall: *showed me three structures* Can you name these structures?
said IP2 & he nearly flipped, corrected myself to IP3.
The other two are Diacylglycerol and cAMP.

Hall: How is cAMP synthesized?
I said from ATP or AMP, not sure, anyway it is cyclysed by adenylylcyclase.

Hall: What is the nucleophile and what the electrophile in the reaction?
I just had to guess, had no idea
Hall: The hydroxy group on the ribose is the nucleophile and the diphosphate leaving group the electrophile (I’m really not sure if I remember this correctly though).

Hall: How can you differentiate between H1 and H2 antagonists?
I talked about how the active site is different and that drugs have different structures depending on what they are trying to inhibit.

Hall: How would you know that a drug binds the H2-receptor over the H1-receptor
I talked about crystallography but he said it’s difficult to crystallize GPCRs bc they are transmembrane molecules. so embedded in the membrane.
I don’t remember the exact answer to this question he gave me though.

Hall: What’s the difference between early and modern drug discovery?
early: target unknown, drugs just tested for their therapeutic effect
modern: target selection and validation first, screening for drugs afterwards

Hall: What’s one downside / risk of modern drug discovery as you just described?
I said that the target validation is a process taking place up until the clinical trials and that one can never be certain if the target is good until tests in human have been carried out.
Hall: What does that mean in regards of risks?
That a financial commitment / time must be invested but we can’t be really sure if the target is actually good.
He kind of didn’t like the answer but accepted it.

Hall: *showed me a picture of a drug* You have probably never seen this before
Nope
Hall: This is *talked about the drug but I don’t even remotely remember what it was*.
Hall: What special structural features does it have?
I said it has quiet a long alkyl chain

Hall: Yes. What does that mean?
It is hydrophobic
Hall: Yes. How do you think the drug is applied?
I said as a topically which he kind of agreed on but clearly wasn’t the answer he was after.

Hall: What is the problem if the drug is hydrophobic?
I said it is poorly soluble in the blood and will distribute quiet badly
Hall: How can we solve that?
Addition of polar groups

Hall: was kind of confused, I was as well
Hall: The alkyl group is a palmitate ester. A palmitate ester of a drug is often used as a prodrug . Why?
Because it is hydrophobic and helps the absorbing the drug in the stomach.
Then it finally clicked and I said after hydrolysis of the palmitate ester is more hydrophilic and therefore better soluble in the blood, leading to better distribution in the body.
He was relieved and I was as well.