A colleague put me onto this paper, which appears in a journal (IUCrJ) that it’s safe to say that I don’t keep up with very closely. The authors, from Rutgers, are looking at fragment screening, and have found that 4-bromopyrazole and 4-iodopyrazole are very odd in that regard. They show up as hits in fragment assays, and soaking them into protein crystals makes it clear that those results are not false positives. The halopyrazoles bind and spare not: in a crystal structure of the complex between HIV reverse transcriptase and the inhibitor rilpivirine, a soak of 4-bromopyrazole revealed fifteen separate binding sites. It alone recapitulated the majority of binding sites found during an entire fragment screening effort.
They tried a number of analogs to see how general this effect was, and only 4-iodopyrazole was comparable. Soaking these into other proteins entirely gave similar results – they didn’t get all the sites identified by a full fragment screen, but they did very well. What’s interesting is that these binding sites were of several different characters (electropositive, electronegative, polar, nonpolar), and the modes of binding were various as well:
We hypothesized that the promiscuous nature of 4-bromopyrazole and 4-iodopyrazole may be owing to the electrostatics and small size of these compounds. These compounds are capable of creating diverse interactions with protein and solvent atoms through a basic chemical scaffold consisting of six non-H atoms that form an aromatic ring with hydrogen-bond donor and acceptor functionality and a halogen, providing diverse contacts with protein atoms and solvent molecules. Density functional theory calculations revealed that the electronegative N atoms in the pyrazole ring enhance the polarization of the Br atom in both negative charge and the positive charge of the `sigma hole’ opposite to the C—Br bond when compared with less electronegative heterocyclic rings. . .
That small donor/acceptor pair motif is indeed found all over the biochemical world, probably because of the ubiquity of amides, esters, carboxylic acids and so on. And it may be that 4-halopyrazoles are just the size and shape to hit a lot of them, with (as mentioned above) the halogen contributing on its own as well.
That’s particularly fortunate for X-ray crystallography, since bromine and iodine atoms provide strong and utterly unmistakeable signs in X-ray data. They’re popular, of course, because if you pick the right wavelengths, you can get anomalous dispersion off of them (you want the math, you say?) that can zip up the phasing problem and (given the fearsome powers of modern software) quite possibly drop your structure right into your lap. Iodine’s especially nice for people who don’t have a synchotron down the block, because the Cu-based X-ray tubes on “home” diffractometers are a good fit for this technique. The authors tried, with some success, to see if a quick soak with these pyrazoles could be used to improve the structure solutions of their protein crystals, and it looks like this idea is well worth adding to the box of tricks. Most med-chem labs will have one or both of these compounds sitting around on the shelf – you do Suzuki couplings, I’ll bet – so the barrier for experimentation is very low indeed.