The last major fragment event of this year is over, but it ends on a high note: FBLD 2010 has remained true to its predecessors in bringing together a great group of fragment enthusiasts in a Gordon-Conference-like environment. With 30 talks and even more posters I won’t attempt to be comprehensive or even representative, but will instead just pick out a few themes. Those of you who were there, please chime in with your own observations.
One of the themes was the shape of chemical space, and what makes a good binder. Jean-Louis Reymond, who has been systematically enumerating all stable molecules containing carbon, nitrogen, oxygen, and a few other atoms, has already published up to 13 heavy atoms but is now expanding his analysis to molecules containing up to 17. The issue of whether more attention should be given to three-dimensional fragments was discussed, with Ken Brameld reporting that fragments in crystal structures at Roche and the protein data bank contain fewer “flat” compounds than does the ZINC database of commercial molecules. However, analyzing 150,000 molecules with MW < 300 that had been screened in 40-100 high-throughput screens at Roche did not show any shape differences between the 50,000 molecules that showed up in at least one screen and those that didn’t. Interestingly, this ratio also came up in a talk by Tony Giannetti of Genentech, who said that across 13 screens 36% of their fragments hit at least one protein, while the rest didn’t hit any. Vernalis has found similar results; is there any way to enrich for the productive binders?
While FBLD 2009 had a strong computational theme, a major thrust of this conference was using biophysics to detect and confirm fragment binding. Tony discussed best-practices in SPR, and noted that since small molecules are “brighter” in NMR assays than proteins it is possible to find even very tiny fragments, including a 6 heavy-atom compound with a Kd of 600 micromolar. Tony also described the use of SPR for weeding out badly behaved compounds. Spookily, he noted that promiscuity is a function of compound, protein, and buffer, so it is not possible to weed out bad actors in a library before screening: one compound that was promiscuous against 8 targets bound legitimately and gave a crystal structure with a ninth. Adam Renslo of the University of California San Francisco described how easy it is to be misled by such phenomena. Glyn Williams described how Astex uses biophysical techniques to detect problem compounds, and noted that oxidizers can be particularly insidious – a trend that will likely continue as people explore novel heterocycles.
Glyn also presented a fascinating if slightly depressing discussion of ligand efficiency. As many have found, it can be challenging to maintain ligand efficiency during the course of fragment optimization. Yet even this goal is too modest. A fragment pays about 4.2 kcal/mol in binding energy when it binds to a protein due to loss of rotational and translational entropy; since this enropy cost is only paid once, atoms added to this molecule do not have this liability . Thus, merely maintaining ligand efficiency means that the atoms being added are binding less efficiently. This point was also emphasized by Colin Groom of the Cambridge Crystallographic Data Centre.
Membrane proteins are increasingly being targeted by fragment-based methods, as recently discussed on this site, and both Gregg Siegal of ZoBio and Rebecca Rich of the University of Utah presented progress against GPCRs.
There was general agreement that many approaches can find fragments, and that using several orthogonal methods is a good way to separate the true binders from the chaff, but a continuing challenge is what to do next. The last two sessions were devoted to chemical follow-up strategies and success stories. Some of these have been at least partially covered on Practical Fragments (for example here, here, and here) but there were a number of unpublished examples too – we’ll try to discuss these individually as they emerge.
If you missed this or the previous two conferences you’ll have another chance in 2012, when the meeting will be held in my fair city of San Francisco. And if you can’t wait that long, there are at least two fragment conferences scheduled for next year – details to come shortly.