Medicinal chemistry exam. 13.8.2021 at 10.30
Exam atmosphere is quite relaxed. At the beginning of the exam he explained to me that the goal is to have a conversation, so I can ask for help if I got stuck and I can't move forward. Not 100% sure that everything I wrote is correct!

Hall: What can you tell me about target validation.
Me: It a phase of drug discovery where the validity of a candidate target of the diseases is confirmed. For example, if during clinical trials is found that, when targeting a target, there is not the hoped physiological effect or any effect at all, then the target is not validated.
Hall: In the lecture we saw the example of the anticancer Imatinib. In this case, after some time patients developed resistance and the drug didn’t have a physiological effect anymore. Are you saying that this target is not valid?
Me: No of course. Then I would say that if targeting a receptor leads to a physiological effect, then the target is validated.
Hall: Oh, you are turning around things then [laughing]. What causes the emerge of resistance for drugs like these (referring to imatinib)?
Me: If there is a mutation in the binding pocket of the drug (which happens relatively fast in cancer cells due to their continuous cell division cycles) and for example some residues that forms a hydrophobic pocket mutate into a more polar or even charged amino acid, the binding affinity of the drug will be considerably reduced. Another example in the case of cancer cells is also when the overexpression of the receptor will make the drug activity vain (since you will need much higher concentrations to inhibit all the targets).
Hall: Yes, I see your point, what you are saying is all correct. In the first case you mentioned (the one with mutated residues in the binding pocket), how can you solve the problem of resistance?
Me: [Guessing] Maybe with crystallization of the mutated receptor you can see which residues are changed and you can modify your drug accordingly.
Hall: You’re confusing with another type of receptor, where co-crystallization was made.

Hall: [he showed me two structures] You have already seen one of these structures, while the other not. [The first one was a quite complex molecule with an 8-membered ring and many substitutions, I would say it was a pleuromutilin derivative. The second structure was Salvarsan]
Me: [not recognizing both structures] The first one reminds me of taxol since it has a similar 8-membered ring, but I’m not sure.
Hall: No this is not taxol, but what have in common with it?
Me: it is probably a natural product due to the complexity of the structure.
Hall: what can you tell me some disadvantages in design such type of structure as drug?
Me: Designing a complex compound is disadvantageous because it will increase time and cost efforts for the chemical synthesis on large scale.
Hall: This is true, but what can you tell me about morphine? It is also a complex molecule. Is it hard to produce too?
Me: no because it is a natural product.
Hall: and what about penicillin? Is it hard to produce penicillin on large scale?
Me: No because a semi-synthetic method is used.
Hall: then there is another major disadvantage of having complex structures, rather than production issue. Can you tell me what it is?
Me: Such large structures are also susceptible to many reactions of the metabolism, and this will complicate a lot the drug discovery project.
Hall: correct.

Hall: what about the second structure? What can you tell me?
Me: I don’t remember this structure.
Hall: It is an ancient antibacterial used to treat syphilis. What are the possible targets to treat a bacterial infection? Can you give some examples?
Me: Penicillins target the bacterial enzyme transpeptidase, which is responsible for the formation of bacterial cell wall.
Hall: correct.
Me: then also the bacterial genome can be targeted
Hall: Yes, but you already told me about the transpeptidase which is part of the bacterial genome.
Me: I can’t remember anything else in this moment…
Hall: You can target bacterial metabolism. We saw many examples in the lecture… What are the advantages and disadvantages of making a drug discovery on antibacterial compared to the drug discovery for example of an antipsychotic?
Me: Bacteria are very different organisms compared to host cells, so it would be easier to develop drugs that are effective just on bacterial cells and not also on eukaryotic host cells (cause fewer side effects).
Hall: Yes, this is a point, even if there are anyway many antibacterials which have many side effects. [It wasn’t what he wanted to hear. He said something like this:] Bacteria have a relatively small genome, therefore almost every protein is very important and can be used as target.

Hall: [Showed me the structure of clavulanic acid] What can you tell me about this structure?
Me: It is a beta-lactamase inhibitor.
Hall: How did you recognize it?
Me: It has the main ground structure as penicillins but it leaks the alpha-functionality, the functionality at C6 [pointing on the draw].
Hall: Correct. What can you tell me about this side? [pointing on the functionality at C3]
Me: [not so sure] Here in penicillins there is usually a double methylation functionality, while in this case we have a sp2 hybridized carbon.
Hall: Yes… well which functional group is this? [pointing towards the O4-C3-C8 centers]
Me: an enol
Hall: Yes. How is the reactivity of the enol?
Me: For example, it can do an Aldol reaction, Claisen condensation, or more in general it acts as a nucleophile so it will react with many different electrophiles (I mentioned carbonyls, alkylation, I wasn’t sure where he wanted me to go)
Hall: Well, we are going a bit too much into chemistry [laughing], I don’t think a Claisen condensation is very common in biological environment.

Hall: [Showed me the structure of a sulphonamide (the one on the left at p. 34 of the lecture slides)] What can you tell me about this drug? Which type of drug is it?
Me: It is a sulphonamide
Hall: How did you recognized it?
Me: Because it is a para-substituted aniline with a sulphone functionality.
Hall: Yes.

Hall: [Showed me a paper with a last structure. Sorry but I don’t remember the name. It had multiple functionalities: an oxime, a tertiary amine, a long alkyl chain connected with an ester bond, …]. You have never seen before this structure. It is an antipsychotic. This is a particular structure for a drug, can you tell me why?
Me: It has a long alkyl chain connected through an ester bond. This is probably cleaved in the blood since ester bond are labile and susceptible to esterases in the serum.
Hall: Why is this functional group useful for?
Me: Is makes the drug much more hydrophobic allowing adsorption in the gut, since it can pass through cell membranes.
Hall: Yes. What can you tell me about metabolic reactions that can occur on the structure?
Me: As already mentioned the esterase will cleave the ester bond. Then, probably the oxime and the tertiary amine will be oxidized.

Time ended