18.08.2021 10:50

The atmosphere was quite relaxed. Hall asked me if I've ever had any oral exams and how it was taking exams over Zoom....

Q = Halls Questions
A = My answers

-my english was quite awful, so the answers are not exactly word by word what I said. I switched to german from time to time as well-
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Q: let's talk about protein-protein interaction. why did I told you guys over the course of this year, that drugs targeting protein-protein interactions are difficult to design?
A: because protein-protein interactions are manifold and take place over a big area of the molecule. designing a drug against / inhibting such interactions would be rather large. larger drugs are difficult / impossible to deliver on site.

Q: what kind of interactions are we talking about?
A: primarly VdW, because the interacting surface area is big, those interactions are more promenent. hydrogen bond interaction play an important role as well.

Q: Why VdW?
A: (Bit confused because I thought I just said that) Because they are more dominant and numberous in larger molecules. Inducing dipol moments.
Q: Yes.

Q: Why is it problematic to design a large drug?
A: It would be basically impossible to deliver it to the site of action. oral availability isn't an option, injection can cause irritation...
Q: Yes, yes I see that. This doesn't answer my question. The answer is way easier.
A: If the drug is large it is metabolized to greater extend. Those metabolites need to be screened and can be toxic...
Q: Or non effective
A: yes

Q: But there are drugs that ihibit drug-drug interaction, name one.
A: Reverse transcriptase inhibitors (wrong of course, I was thinking about protease)
Q: I have shown many structures in my lecture, never have I showed you an inhibitor of RT on a protein bases.
A: I think I'm confusing things here... yes, I meant Peptidase
Q: You mean Protease, but no.
A: I'm stuck, I can't give you an answer right now.
Q: Paclitaxel what does it do?
A: Ah, it's a natural drug, inhibiting the depolarisation of microtubuli.

Q: So it's a natural protein-protein interaction inhibitor. how is that possible?
A: Because of co-evolution, for example...
Q: So nature is not interested about complex structure it just does its thing.

Q: Ok lets move on target validation, what is it?
A: It is one of the first things done in drug discovery. you want to find targets that are linked to the disease mechanism and are drugable, as well as provide a therapeutic effect. But target validation is an ongoing process taking place over the whole drug development process. even in clinical trials, the target might be invalidated, if it shows some toxic side effects or simply does not provide a therapeutic effect, better than the standard therapy option.
Q: Yes. but what is different in target validation in preclinical vs clinical.
A: Preclinical wants to know the structure of the target to be able to design against it. but now we are again at lead development and I think that's not what you want to hear.
Q: yes it is not
A: well in preclinical you have the options to analyze your target, to improve pharmakodynamics of your lead. In clinical trials this is no longer possible and failure there are problems of either pharmakodynamics or pharmakokinetics.
Q: true. but how does it come that a drug shows activity in preclinical trials and clinical trials but suddenly in phase 3 trials no more.
A: (not sure what I said here)
Q: I talked about a drug in the lectures (I have never heard of anything he's speaking about). So how come the drug does no longer work?
A: Because of resistance? Cancerous cells have high proliferation and mutation and can render a drug ineffective.
Q: Yes, but we are talking about EGFR (I did not know we were talking about that). Why does it no longer work?
A: Because of natural selection. the cancerous cells can mutated and cells that do no longer need a specific factor overtake the population.
Q: Of course, but be more specific about the binding site.
A: The binding site can mutate and
Q: Yes mutation in the binding site. Name some of them.
A: If you have an ionic interaction, between lets say a caboxylic group and a charged amin group, the binding site might be mutated in a way, so that the polar amin is substituted with a apolar group.
Q: exactly, what else
A: (long think) there could be a sterical hindrance, so that the drug can no longer bind, because the binding pocket is too small.
Q: Yes (and starts to explain it)

Q: Now I have here a molecule you have never seen before. I think it is for diabetes. (Clock rings, but we keep going). Tell me what ideas chemists had in mind designing such a drug.
A: Speaking about all the different functional groups and naming them. Oral uptake might be difficult since it has so many different polar groups, but it doesn't have to be oral though since it is a drug for diabetes
Q: But it would be nice
A: yes.
Q: where is metabolism happening here
A: (thinking) I'm struggling to find anything, all the groups seem pretty stable
Q: what are you looking for?
A: oxidation, but I can't find a group that is beeing oxidised easy
Q: what about the hydroxy groupe there?
A: ah yes, could be oxidated into an aldehyde and further into carboxylic acid
Q: And there is stops
A: No, it can be glucuronated (I couldn't pronounce it and said I hope he knows what I mean. He laughs and says, he cant either pronounce it)
Q: What about chloride, what is the idea?
A: normally a good leaving group, but on an aromatic ring not really
Q: so what is it then?
A: Probably a bioisoster
Q: what are bioisosters?
A: functional groups that are interchangable withought changing the steric properties to much. The hydroxy groups can be changed for an primary amine or a methyl group
Q: yes and the chloride
A: well I guess it could be a hydroxy group isoster
Q: what about methyl
A: could be as well, bioisosters are not limited to one functional group only
Q: they are not limited to one group, yes

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I think I had more like 25-27 minutes of exam time