The latest issue of Prog. Biophys. Mol. Biol. includes five articles on fragment-related topics. We already discussed one from Astex; brief summaries of the rest follow.
Eddy Arnold (who has an editorial introducing the articles) and colleagues from
discuss the advantages of screening fragments crystallographically. Regular
readers of this blog will likely be familiar with some of the material, but
there is lots of practical advice on fragment cocktail design (that is,
choosing which fragments to mix together), optimization of soaking,
high-throughput crystallography, and related topics. There is also a nice
example of an “unknown known,” where the apparent activity of a compound turned
out to be due to contaminating metal. Rutgers University
David Dias (University of Cambridge) and Alessio Ciulli (University of Dundee) have a piece on using NMR in structure-based lead discovery, with a heavy focus on large multi-protein complexes. They succinctly review both ligand-based and protein-based NMR methods and then discuss how these techniques can help determine ligand conformations and binding sites. Next, they discuss how to tackle high molecular weight protein assemblies or protein-protein complexes, often by using clever isotopic labeling strategies. The figures throughout are particularly effective at showing what kinds of information can be obtained from the various techniques.
Andrew Hopkins (
and colleagues are up next with “Fragment screening by SPR and advanced application to GPCRs”. Surface plasmon resonance, of course, is a mainstay of
fragment screening, and this is a timely how-to guide by some of the experts in
the field. As the title suggests, a major focus is on GPCRs, a class of
membrane proteins only recently targeted by fragments. There are some good
practical tips on protein immobilization, screening, and weeding out false
positives. My sense is that screening GPCRs by SPR remains challenging; most of
the fragment libraries screened tend to be small (no more than a few hundred
compounds), and sensitivity seems to be an issue, with most of the hits being
quite potent by the standards of FBLD (low micromolar or better). University of Dundee
Finally, Theresa Tiefenbrunn and C. David Stout (Scripps) lead us “Towards novel therapeutics for HIV through fragment-based screening and drug design.” Practical Fragments has highlighted fragment efforts against several targets for this virus, including HIV protease, HIV reverse transcriptase, HIV integrase, and TAR RNA; this paper discusses these and more. This is a thorough compilation of copious data and focuses heavily on fragment screening. Crystallography plays a starring role, but SPR and NMR are also prominent. In short, it shows practical applications of the prior papers, and so makes a nice conclusion to this series.