Explaining the IC50 of these isosteres

[mycotheology]

Heres the question:
http://img52.imageshack.us/img52/8328/screening.png
and here's another question of the same type:
http://img341.imageshack.us/img341/4712/screening2.png
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.

 

[jbsteele]

The main difference between the two questions is the nature of the functional group at the site of substitution. In question 1, the most potent isostere has an ether functional group, while the least potent one has a sulfide group. In question 2, the most potent isostere has a secondary amine group, while the least potent one has a tertiary amine group. The ether functional group in question 1 has a larger size than the sulfide functional group, so it can potentially interact better with the receptor molecule and hence is more potent. On the other hand, the secondary amine functional group in question 2 has a smaller size than the tertiary amine functional group, so it can potentially interact better with the receptor molecule and hence is more potent. Another factor to consider is the charge distribution of the functional groups. The sulfide functional group has a negative charge, while the tertiary amine functional group has a positive charge. These charges could potentially affect the interaction with the receptor molecule and influence the potency of the drug. In conclusion, the size and charge distribution of the functional groups at the site of substitution can affect the potency of the drug by influencing its interaction with the receptor molecule.