[mycotheologist]

Heres the question:

Firstly does anyone know what Ki is? Ionisation constant? I'm guessing its proportional to the drugs potency. I could take a good guess by observing the differences between each isostere but I'm guessing theres some kind of method I should be able to use here.

[discodermolide]

Heres the question:

Firstly does anyone know what Ki is? Ionisation constant? I'm guessing its proportional to the drugs potency. I could take a good guess by observing the differences between each isostere but I'm guessing theres some kind of method I should be able to use here.

K_i is probably the binding constant to the receptor. It looks as if the following part structure could be the pharmacophore.

[mycotheologist]

Thanks but what reasoning was behind you determining the pharmacophore? The molecule on the bottom left is identical to your proposed pharmacophore and I see that it has a higher K_I than captopril. I'm guessing that this is because the ring on capropril makes the molecule more rigid and thus, eliminates less potent conformers.

Since the top right and bottom right isosteres are far less potent than captopril, I suppose that makes it clear that the CO₂H group is part of the pharmacophore. I suppose the fact that the 2nd and 3rd left isosteres have an extreme difference in potency is evidence that the CH3 group attached to the chiral carbon is part of the pharmacophore.

Heres another one of these questions:

can you tell me if I have the right idea here. The reason compound 7 is 5 times more active is either because the smaller ring allows it to fit into the receptor better (less steric hindrance) or the smaller ring makes the molecule more rigid. The N-methyl group on compound 2 either causes steric hindrance or it makes the compound too hydrophobic to be distributed effectively. If the latter were the case though, I'd assume compound 3 would also have reduced activity. I can't really see the former being the case either though because how much steric hindrance can a single methyl group cause? Heres my guess as to what the pharmacophore is:

but I still don't really know what I'm doing. I need a system. See the way the show one isostere with an F atom attached to the benzene ring and this isostere exhibits no difference in activity. What is that supposed to tell me?

[discodermolide]

You are probably correct about compound 5, the smaller ring can fit into the binding site more easier. I would suggest that the N-methyl in compound 2 removes one of the binding components, the amide NH, the other aromatic NH is not relevant for binding as shown by compound 3.
If you remove the carbonyl and add the fluorine you get the same activity, the fluorine may reach another pocket where is can H-bond with an amino acid there, or an OH group.
So in your pharmacophore I would put a hydrogen bond acceptor on the para position of the phenyl ring. But we really need more information about that position to be sure.
I don't think there is a system you need to look carefully at the SAR of a series to determine the pharmacophore.

[Babcock_Hall]

Biochemists often use dissociation constants (symbolized by Ki), as opposed to association constants.  Smaller dissociation constants are associated with stronger binding.