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The Latest Protein-Protein Compounds

Here’s a review of protein-protein interaction “hot spots” and their application to drug discovery. There have been several overviews like this over the years. This one doesn’t break much new ground, but it does provide a number of recent examples, all in one place.
People approach this subject because of its intrinsic interest (how proteins interact), and in hopes of finding small molecules that can interfere. The hot spot concept meshes well with the latter – if there’s some key interaction, then you have a much better chance of messing with it via a drug-like molecule, compared to the one-wrinkled-surface-approaching-another-one mode of binding. There are probably no examples at either pure end of that continuum. Alanine scanning of a protein-protein interaction will always, I think, tell you that some residues are more important than others. But are they important enough that disrupting just that one would mess up the whole binding event? And (a bigger problem) is there any reason for a small molecule to be there in the first place? That’s the real kicker, because while there are probably plenty of PPIs that wouldn’t take place if you jammed a 350-MW small molecule into the middle of them, there aren’t as many protein surfaces offering enough binding energy for the small molecule to want to do that.
And that word “small” probably needs to be in quotation marks. One excuse for the low hit rates in screening such things has been that existing compound libraries aren’t stocked with the sorts of structures that are more likely to hit. I’m not sure how valid this argument is. It’s the sort of statement that’s very close to tautology: the reason we didn’t find any good hits in the screen is because we don’t have good hit compounds – thanks! But there may well be structural biases as you go towards protein-surface binders – big lunker molecules with lots of aryl rings, if this attempt to calculate their properties is valid. Now, I don’t know about your screening libraries, but the ones I’ve worked with already seem to have plenty of big flattish things in them already, so you still wonder a bit. But it does seem as if this area has a significantly greater chance of posing PK and formulation challenges, even if you do find something. The struggle continues.

4 comments on “The Latest Protein-Protein Compounds”

  1. Justin says:

    This was essentially my PD work, and you’re right, lots of flat molecules and peptide-like structures to form the beta-sheet interactions. It’s fun, if you’re an academic. For Pharma, not so fun. The typical library screening isn’t likely to yield much. Rational design is what is needed, but then you end up with undrug-like beasts. Not impossible, but a tough road, and not one I wish on anyone.

  2. Anonymous says:

    typically, small molecules work best when targeting sites on proteins where other small molecules or small peptides bind.
    for larger flat PPIs, small molecules are not the right tool for the job. Not so surprising in hindsight.

  3. Texascarbon says:

    …. What about allosteric modulators of PPIs. People like to talk about them, but how do you find them…..

  4. Fibrinolysis says:

    The drug tranexamic acid is seldom mentioned in these kind of discussions. It’s small as a fragment. If the standard screening collections don’t include small “hit” molecules…then fragment collections might. Isn’t there a promising fragment-based PPI initiative on going somewhere in California?

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