17.08.21
13.20

Q: What are examples of drugs that are gained through semi-synthesis
A: Penicillin and morphin
Q: Only, morphin derivatives
A: Right, mostly natural drugs that have very complex structures where de novo synthesis is not feasible and a natural product starting molecule is used and adjusted according to demand with synthetic measures.
Q: *draw a binding pocket and drug with a hydroxy group* This hydroxy group binds through hydrogen bonding to the protein. How can you be sure that it is hydrogen bonding
A: Da hatte ich kleine Probleme habe nicht sofort die Anwort gewusst, die er wollte (Chlorid isostere, da keine H bonding eingehen kann. Habe über nur hydrogen, methoxy, amine gesprochen und erklärt was die Effekt davon auf die Bindung wären. Am Ende hat er gesagt was mit Chlorid sei und habs dann erklärt.
Q: Topic peptic ulcers what do you know?
A: receptors: histamine, acetylcholine, gastrin; proton pumps; antibiotics
Q: you mentioned histamine here are the gpcr. *shows table* what can you say from this
A: Gs und Gq und wie die Signalkaskade geht
Q: can you draw ATP and how it is converted to cAMP. what is the leaving group?
A: yup, diphosphate
Q: this is cimetidine. It was developed from the natural ligand. Why can this approach be advantageous
A: You know the starting point, and through rational design you can add groups and determine the pharmacophore and see what increase/decrease activity or acts as antagonist/agonist
Q: in cimetidine what is the function of the nitrile
A: first thiourea (toxic) -> guanidine (too basic) -> cyano group electron withdrawing (lower pka)
Q: electron withdrawing groups. What other groups could be used
A: nitro
Q: cimetidine acts on metabolic enzymes. what can you tell me about drug-drug interactions
A: certain drugs induce or inhibit the activity of metabolic enzymes which can have an impact on activity or toxicity. Specifically cytochrome p450 enz are susceptible to this
Q:*shows drug with long alkylester* this is a peculiar structure.
A: yes it has a long alkyl chain connected to an ester. This is done to reduce hydrophilicity and improve absorption in the gut. The ester is then cleaved in the blood.
Q: yes and no. the ester masks the hydroxy group and doesn’t need a long chain to reduce the hydrophilicy.
A: ahh so it is to make sure it localizes to fatty tissue like the brain or adipose tissue.
Q: the palmitate acts as a sort of sustained release where it is stored in depots and the hydrolysis is rather slow. It is an antipsychotic. The actual drug that is active is a metabolite of the administered drug. How do you imagine this drug was discovered.
A: the old approach of drug discovery as modern mthods. i.e hts would not be able to find hits for metabolites. Old approach of giving a drug and observing the effects on the organism.
Q: yup. Times up
A: :)
Q: :)

18.8.2021 8:45

You come in, show your student card to the assistant, write your name and date on the top of a piece of paper and he explains to you that he’d like to have a discussion.
H: What is the problem with Protein-Protein Interaction?
-He wants to hear about complexation, that they get very large and block the binding site for the drug (there are drugs that can go into the binding side or slide between the two proteins to hinder complex formation). I mentioned natural compounds, so his follow up question was:
H: Can you tell me about the advantages and disadvantages of natural compounds?
-evolutionary proved that it works, biological systems can make very complex structures a chemist would never think of. Disadvantages are not synthesisable economically on large scale, very complex, not stable. Mention semi-synthesis.
H: Can you tell me examples of natural compounds?
-Taxol, Curare, Penicillin
H: What is target validation
-A process that enforces you that you’re on the right way in the process, the stages of development
H: I talked about XY in the lecture (slightly panicking because I have never heard that name before) and how it is a kinase used in cancer. What do you recall?
-That this was a surprise because kinases weren’t considered a good drug target because they are ubiquitous.
H: What’s a problem with kinases and cancer, more specifically with cancer as a drug target?
-Mutate quickly
H: How would you solve that?
-Scaffold hopping (he was amused by that?), analysing the target to see which amino acid residues were mutated. He mentioned that in vivo analysis is quit good nowadays, but you’d have to go through all of the clinical phases again.
H: Why did this kinase validate the target?
-Since the virus mutated it, it needed to be important. (There was probably a more sophisticated answer to that but he moved on)
H: You have probably never seen this molecule before: shows me Fingolimod.
-I knew the drug from Immunology so I talked about the fact that it was used for graft rejection and interacts with autoreactive T-cells who interact with the foreign MHC of the Donor cells. He added that it is also used in Multiple sclerosis. I thought out loud about what multiple sclerosis was and then I mentioned that the same thing happened with H-2 Blockers that were first designed to help with gastric ulcer but then proofed to be good antiemetics. He then explained to me how it happened that the indication changed (I absolutely do not recall that answer).
The alarm ringed but he wanted to talk about the structure of Fingolimod a bit so I talked about hydrolysis (not happening), but that it has a lot of possible places where it could oxidate. He then mentioned that he always thought that this drug would be an absolute nightmare but yet it’s a billion-dollar drug.
With that, the exam ended. I didn’t have to draw anything but had to hand in the empty paper anyways.
Just tell him everything you know, if it isn’t the thing he wants to hear, he will tell you and try to navigate you in the right direction.

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