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A Tour of the Outer Precincts

You know, in an odd way, I’m actually more optimistic about drug discovery than I was a few years back. It’s due to the new tools that we have in molecular and cellular biology that we didn’t have before, and it’s also the number of unusual and interesting approaches that are being taken on the chemistry end of things. For many years now, we’ve all been saying “Yep, protein-protein interactions. Transcription factors. All that stuff. Gotta find a way to deal with those at some point.”

But trying to use straight-out small molecule screening against the harder modes of action didn’t lead to a lot of notable progress. That led to disconcerting thoughts from small-molecule drug discovery chemists about what the future might hold if (as it looked) a lot of potential target space didn’t have room for what they did best. I think that those worries were well-founded, because I think it’s true that a lot of (potential) target space gets increasingly hard to address with traditional med-chem molecules. And while there are exceptions, they may not be enough to make a living off of.

One answer, then, has been to move beyond those traditional molecules. To that end, I’d like to recommend this new review article in Angewandte Chemie, on “New Modalities for Challenging Targets in Drug Discovery”. It’s a useful summary of recent work on a whole list of attempts to go after protein-protein targets and other tough mechanisms, and it covers, systematically, a number of increasingly out-there compound classes. You’ll find stabilized peptides, macrocycles, protein-small molecule hybrids of all sorts, oligonucleotide derivatives, and more. I’m quite grateful to the authors for having taken the effort to bring this far-flung pile of literature all into one place.

Are these sorts of molecules going to solve all your problems? Not at all. In fact, if you pick the wrong class, they could make your life noticeably worse. But if instead, you’re just going to run the small-molecule screening deck past the sorts of targets these things are applied to, you’re not going to have a very good time of it, either. (Prepare yourself for “False Positives for $1000, Alex”, and the longest round of Double Jeopardy you’ve ever seen). I can’t say that I would recommend running a whole drug discovery department with this sort of chemical matter alone, any more than I would recommend adding a cup of Tabasco sauce to a batch of soup. But if you’re going to go after some of these harder mechanisms – and eventually, you probably are – then you’re going to have to be ready to use any weapon that comes to hand. Some of these binding surfaces are not going to yield to anything less, is my guess.

So even if you’re not going to rush out right now and start making bicyclic peptides or nanobody-drug conjugates or whatever, give this review a look. It’s a tour of some areas of chemical space that you probably have never had a chance to visit. But who knows – you might end up heading that way some day.

10 comments on “A Tour of the Outer Precincts”

  1. David Antonini says:

    A cup of Tabasco in a batch of soup doesn’t sound like a bad idea here! Particularly if you’re making 10 or 20 quarts.

    1. Jackass says:

      Preach bother!!!!

    2. BK says:

      Chipotle Tabasco is the only way I roll.

  2. JB says:

    What do you think about this data dump Derek?

    https://www.poisonpapers.org/

  3. chemical biologist says:

    My personal record was to conjugate carbohydrate to mixed peptide/peptoid backbone and attach modified RNA to that. It had MW of 3.9 kDa but still was called small molecule and didn’t do what was expected 🙁

    1. Putmebackinfrontofthehood says:

      a good example of the still yet to be explored “chemical space” out there

      Lots and lots of work for chemists!

  4. Bill says:

    We dont need more molecules–we need more ways to control the molecules we have. Eg. molecular machines—- synthesis is dead. Synthetic chemistry is dead. Chemistry departments should be dismantled.

    1. Pennpenn says:

      I suppose the resulting puzzle would be figuring out how to make molecular machines without “new molecules”, or any form of synthesis, or chemistry (departments). Voodoo perhaps?

      1. b says:

        Synthesis machine, duh.

  5. Anon says:

    Great, does any one has any idea or statistics out there that compares drug discovery chances as a result of serendipity and logical thinking drug discovery with all those tools available?

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