There are a huge number of techniques in the protein world that relay on tying down some binding partner onto some kind of solid support. When you’re talking about immobilizing proteins, that’s one thing – they’re large beasts, and presumably there’s some tether that can be bonded to them to string off to a solid bead or chip. It’s certainly not always easy, but generally can be done, often after some experimentation with the length of the linker, its composition, and the chemistry used to attach it.
But there are also plenty of ideas out there that call for doing the same sort of thing to small molecules. The first thing that comes to mind is affinity chromatography – take some small molecule that you know binds to a given protein or class of proteins well, attach it to some solid resin or the like, and then pour a bunch of mixed proteins over it. In theory, the binding partner will stick to its ligand as it finds it, everything else will wash off, and now you’ve got pure protein (or a pure group of related proteins) isolated and ready to be analyzed. Well, maybe after you find a way to get them off the solid support as well.
That illustrates one experimental consideration with these ideas. You want the association between the binding partners to be strong enough to be useful, but (in many cases) not so incredibly strong that it can never be broken up again. There are a lot of biomolecule purification methods that rely on just these sorts of interactions, but those often use some well-worked-out binding pair that you introduce into the proteins artificially. Doing it on native proteins, with small molecules that you just dreamed up, is quite another thing.
But that would be very useful indeed, if you could get it work reliably. There are techniques available like surface plasmon resonance, which can tell with great sensitivity if something is sticking close to a solid surface. At least one whole company (Graffinity) has been trying to make a living by (among other things) attaching screening libraries of small molecules to SPR chips, and flowing proteins of interest over them to look for structural lead ideas.
And Stuart Schreiber and his collaborators at the Broad Institute have been working on the immobilized-small-molecule idea as well, trying different methods of attaching compound libraries to various solid supports. They’re looking for molecules that disrupt some very tough (but very interesting) biological processes, and have reported some successes in protein-protein interactions, a notoriously tempting (and notoriously hard) area for small-molecule drug discovery.
The big problem that people tend to have with all these ideas – and I’m one of those people, in the end – is that it’s hard to see how you can rope small molecules to a solid support without changing their character. After all, we don’t have anything smaller than atoms to make the ropes out of. It’s one thing to do this to a protein – that’ll look like a tangle of yarn with a small length of it stretching out to the side. But on the small molecule scale, it’s a bit like putting a hamster on a collar and leash designed for a Doberman. Mr. Hamster is not going to be able to enjoy his former freedom of movement, and a blindfolded person might, on picking him up, have difficulty recognizing his essential hamsterhood.
There's also the problem of how you attach that leash and collar, even if you decide that you can put up with it once it's on. Making an array of peptides on a solid support is all well and good - peptides have convenient handles at both ends, and there are a lot of well-worked-out reactions to attach things to them. But small molecules come in all sorts of shapes, sizes, and combinations of functional groups (at least, they'd better if you're hoping to see some screening hits with them). Trying to attach such a heterogeneous lot of stuff through a defined chemical ligation is challenging, and I think that the challenge is too often met by making the compound set less diverse. And after seeing how much my molecules can be affected by adding just one methyl group in the right (or wrong) place, I’m not so sure that I understand the best way to attach them to beads.
So I’m going to keep reading the tethered-small-molecule-library literature, and keep an eye on its progress. But I worry that I’m just reading about the successes, and not hearing as much about the dead ends. (That’s how the rest of the literature tends to work, anyway). For those who want to catch up with this area, here's a Royal Society review from Angela Koehler and co-workers at the Broad that'll get you up to speed. It's a high-risk, high-reward research area, for sure, so I'll always have some sympathy for it.