Dan and I don't see every fragment paper and so it's nice when people point out papers to us. Its typically their recently published paper and they are looking for some sort of recognition/validation from us. Sometimes its a paper we have on our radar, sometimes it isn't. Recently, I received an email pointing out this paper from someone I met at FBLD2014. Well, this is a follow up paper to a paper I discussed a few years back. The title of the post sums up my thoughts: "Another (Impractical) NMR Method." One comment from that post (by a co-author from Astex on the current paper) was
This is a relaxation filtered ligand based method (like T1rho or selective T1). You therefore may consider using it in competition mode if you find one suitable "spy" molecule: this would allow with a single point experiment screening mixtures and/or ranking for low affinity hits(especially if solubility is limiting). I would actually give it a try.
So, it looks like she did. The advantages of Long Lived States (LLS) NMR is that the the dynamic range is wider and it works at low protein concentrations (3 uM or roughly the same as STD or WaterLOGSY) or with very weak affinities. Against the workhorse HSP90 system, they screened mixtures using LLS and a spy molecule.
I still don't think this is a very practical method because it still requires a lot of tailoring to individual systems; in particular the compounds need pairs of protons which are suitable for excitation to the LLS. Using it in "spy" mode gets around this. I would still hold that this is an impractical NMR method. I like to see people developing new methods and trying to improve them. We also need people doing good comparisons of "standard" experiments to new ones. (Here is how NOT to do a method comparison.) I won't dismiss this out of hand, but there is still a lot of work to be done here to move it into a "front line" screening technique.
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