A post had been made about enzyme thermodynamics in which the poster asked about entropic and enthalpic effects of ligands and enzymes. Below is my contribution to this discussion.
Quote from: Doc Oc
I read an interesting review a while ago talking about this. The gist of it was that if you run an assay and collect a bunch of hits, your time is best spent working on the ones with the best enthalpic contribution. The entropic part is the one that is more easily controlled (ie; cyclizing a structure, adding functional groups to control conformation or increase lipophilicity, etc). The enthalpy, however, is something that doesn’t have as good of a roadmap to optimization, so it’s best to pick a compound with a strong contribution there. I’ll see if I can dig that up and I’ll post the reference here.
I agree with the point being made here. I too had reached that conclusion. I was in the ag area and it was common to see a relatively small number of modes of action to be found from screening compounds. This is how I reasoned it.
Linus Pauling has advanced a model that enzymes catalyze reactions by reducing the activation energy of reactions. (I am presuming this is largely an enthalpic effect.) He then argued that mimics of transition states may serve as inhibitors of a reaction. I consider this to be the working paradigm for the modern pharmaceutical industry.
If you put those two facts together, then you should conclude that when you screen for inhibitors, you are actually screening for high activation energy reactions. That is, enzymes that catalyze high activation energy reactions could have the tightest binding constants. The reduction in the activation energy should be proportional to the degree to which the compound is bound to the enzyme. That would explain why a small number of modes of action should turn up most frequently, they must catalyze high activation energy reactions, and therefore have great affinity for their substrates and inhibitors. Therefore, even relatively poor mimics should still inhibit a reaction. It also follows that hard working enzymes will be more promiscuous than enzymes for reactions with lower activation energies.
This line of thinking also raises a temporal aspect of enzyme catalysis. This could be important as one encounters, slow tight binding enzymes. This Pauling model enables one to understand enzyme turnover. The transition state is bound more tightly that substrate or product. Since that is the case, then the relatively lower affinity of substrate and product allows their exchange. Tight binding of a substrate or product should inhibit an enzyme also. It would seem then that a slow reaction should appear to have a high affinity while a fast reaction should appear to have a lower affinity. This is something I was interested in modeling, but I don’t know if that is actually true or useful. That is, tight binding may simply be tight binding and velocity may not matter at all.