Medizinische Chemie I & II
10. August 2021


Introduction:


Tell me about what is a good drug
I explained how the structure should be considering Lipinski’s rule of 5. He wanted more general information and mentioned PK and PD. First he wanted me to explain everything that has to do with PK. I said ADMET and explained each. Absorption with Lipinskis rule of 5, oral bioavailability, Metabolism Phase I and II. He wanted to hear more about PK but I didn’t know what to add.
Then he started talking about PD and the interactions of a drug in its binding site
What leads to high binding affinity?
I said interactions between the amino acid residues of a target and the drug structure.
He asked why would a chemist want a drug not to be polar and orally bioavailable?
I answered that if you don’t want that it acts in the whole body, only where it was locally delivered. To reduce on-target toxicity (same receptors in other tissues)
What he wanted to hear: application of balms on the skin where it only acts in this area



Main thema: Cholinergic receptors

Q: Tell me about cholinergic receptors
A: There are nicotinic and muscarinic receptors with acetylcholine as natural ligand and nicotine and muscarine as agonists (i said antagonist but he corrected me and I explained why agonist is correct in this case)
He said muscarinic receptors are GPCRs and I said nicotinic receptors are ion channels
He asked what the two targets are
I said either the cholinergic receptors or acetylcholinesterase


He showed me the structure of acetylcholine in the acetylcholinesterase binding pocket
He wanted to know everything about the binding interactions at the positive N-atom.
I said ionic interactions with either glutamic or aspartic acid but also cation-pi interactions
He showed me the amino acid structures and wanted to know which amino acid (Phenylalanin, Tyrosin, Histidin) can provide the strongest cation-pi interactions.
I did not know but then we discussed about the hydroxyl group on tyrosine and he helped me with this but the final answer was that as hydroxyl is an electron donating group it pushes more electrons into the aromatic ring leading to a higher electron density and thus to a stronger cation-pi binding.

Then he showed me the structure of apixaban (anticoagulant) and wanted to know what happens in the metabolism.
I first saw the ether group which I said would be demethylated to the hydroxyl by Cyp450 (Phase I metabolism)
Then I started talking about the amides but I thought they would rather not be metabolised because you need harsh conditions to hydrolyse amides but he said this is only a problem in the lab but not in vivo. Then he asked me how many amides there are. Three. He said it was very likely that metabolism at the amides happen.
He wanted to know more metabolism. I said maybe oxidation at the aromatic ring which could be stopped by introducing a fluoride as bioisoster. He asked where? (ortho, meta, para to the ether) I said normally para but not possible because there is already a bond at this place so I said ortho. He was happy with this answer but asked what could be problems after introducing a F-atom. I said maybe the demethylase could not interact properly because of steric hindrance but this was not correct because F is rather small. He wanted me to say sth about cation-pi interactions (again) and I said they would be less strong as fluor is a sigma acceptor and removes electron density from the ring. This was correct (if there would be cation-pi interactions at all)