[mycotheologist]

Heres the question:

and heres another question of the same type:

so the IC50 of a compound is the concentration at which it inhibits 50% of the receptor molecules activity, therefore a lower IC50 means a more potent drug. I'm completely lost on this one. In the first question, the most potent isostere has an ether functional group, while the least potent one has a sulfide group. I know that R-O-R groups are way more stable than R-S-R groups so a possibility that comes to mind is that the sulfide isostere is easily metabolised but question 2 refutes that theory. In question 2, the most potent isostere has a secondary amine group. The tertiary amine is the least potent isostere. Could it be that the S atom is so large that it makes it difficult for the molecule to fit into the receptor? That would explain why the tertiary amine is less potent but it doesn't explain why the secondary amine is more potent than the ether in question 2, while its the other way around in question 1.

[discodermolide]

Question 1
I think it is a question of oxygen being a better H-bond acceptor. You get a slight drop off in binding with the N-methyl compound but not much. Replacement by oxygen obviously finds another binding site.
In the other example it seems to be that there is only 1 H-bonding site available on the receptor.

[Babcock_Hall]

Mycotheologist,

In the top example, I agree with discodermolide that there is a difference in hydrogen bond accepting abilities, but S also has longer bond lengths and more acute bond angles than O.  In the bottom example, which functional group can be a H-bond donor?

[discodermolide]

In the top example, I agree that there is a difference in hydrogen bond accepting abilities, but S also has longer bond lengths and more acute bond angles than O.  In the bottom example, which molecule can be a H-bond donor?

It is those properties of S that make it weaker in these systems. Plus it is not a good H bond acceptor, not so electronegative as O.
An H bond donor is the IC50 = 60nM compound on the left.