In the Northern Hemisphere the winter solstice has passed but the days are still short, and 2015 is hurtling into history. As we did in 2014, 2013, and 2012, Practical Fragments will spend this last post of the year highlighting notable events as well as reviews we didn't previously cover.
Two major conferences this year were CHI’s Tenth Annual FBDD meeting in San Diego (discussed here and here) and Pacifichem 2015. If you missed these don’t worry – we’ll have an updated list of 2016 events soon.
After a three year drought, two new books published in 2015: Fragment-based methods in drug discovery and Fragment-based drug discovery. And the trend looks set to continue, with a new book edited by Wolfgang Jahnke and me set to publish in early 2016.
In addition to complete books, several book chapters may be of interest to readers, the first being “Fragment-based drug discovery” by Jean-Paul Renaud and NovAliX colleagues, published in Small molecule medicinal chemistry (Wiley). This is a general review of the topic, focused heavily on biophysical techniques, especially SPR, NMR, and native MS. It also includes a couple case studies – one on the clinical compound AT9283 and one on the bromodomain BRD2.
The next three chapters all come from Springer’s massive Methods in molecular biology series. Continuing the biophysical theme is “Biophysical methods for identifying fragment-based inhibitors of protein-protein interactions,” by Michelle Arkin and colleagues at UCSF. This provides background and step-by-step instructions for SPR, differential scanning fluorimetry (DSF), NMR (including STD, WaterLOGSY, and HSQC/HMQC), and X-ray crystallography. A more detailed guide to STD NMR is provided by Hai-Young Kim and Daniel Wyss (Merck) in “NMR screening in fragment-based drug design: a practical guide,” while Byeonggu Han and Hee-Chul Ahn (Dongguk University-Seoul) discuss STD NMR applied to kinases in “Recombinant Kinase Production and Fragment Screening by NMR Spectroscopy.”
Moving on to journals, two reviews focus on protein-protein interactions. The first, by Thomas Magee (Pfizer) in Bioorg. Med. Chem. Lett., briefly touches on challenges and solutions before focusing on several case studies, including navitoclax, Mcl-1, RPA, KRas, Rad, bromodomains, XIAP, HCV NS3, and more. The second, by Chunquan Sheng (Second Military Medical University, Shanghai), Wei Wang (University of New Mexico and East China University of Science and Technology) and colleagues is published in Chem. Soc. Rev. This is much broader, covering not just fragment-based approaches but others as well, and includes 229 references and 21 figures. There’s a lot of good stuff in this paper, but unfortunately the authors do not discuss the numerous false positives that can occur, such as aggregation and PAINS, and some of their examples are artifacts. Caveat lector.
The next two papers focus on specific therapeutic areas. Xinyong Liu and colleagues at Shandong University discuss the application of fragment approaches to HIV targets in Expert Opin. Drug Discov. In addition to recent examples, this covers some of the older literature, as well as less conventional topics such as dynamic combinatorial chemistry. And in Front. Neurol., Jeffry Madura and Christopher Surratt (Duquesne University) discuss the role fragment-based approaches can play in developing drugs that target the central nervous system (CNS). This review is particularly focused on computational methods.
The next three papers continue the computational theme. Dima Kozakov, Adrian Whitty, Sandor Vajda (Boston University) and co-workers have two reviews discussing work we highlighted earlier this year. The first, in Trends Pharmacol. Sci., is an excellent summary of how computational hot spot analysis can predict whether a protein will be ligandable, and includes a number of case studies. The second, a Perspective in J. Med. Chem., is a much more wide-ranging analysis of the approach. This paper also considers difficult targets, some of which may be tackled with larger molecules such as macrocycles, and others of which may simply not be druggable. And in Chem. Biol. Drug Des., Matthew Bartolowits and V. Jo Davisson (Purdue University), focus on “subpockets,” which are essentially the regions surrounding individual amino acid residues in proteins. This paper also includes an extensive list of software tools for analyzing binding sites.
Finally, Chris Murray and David Rees (Astex) have a brief but lively essay in Angew. Chem. Int. Ed. After providing essentially a target product profile for an ideal fragment, they challenge chemists to devise new routes to superior fragments. Although fragments may seem simple, the “precision synthesis” required to elaborate them “is often rate-limiting.” Diversity-oriented synthesis (DOS) is one potential solution, although there does not seem to have been as much activity here as might have been hoped. Some of the problems are prosaic but significant: as we’ve noted, highly water soluble fragments can be hard to isolate. The authors call for new synthetic methodology compatible with small fragments containing diverse hydrogen-bonding functional groups.
And with that, Practical Fragments says farewell for the year. Thanks for reading (and especially for commenting) and may 2016 bring brilliant breakthroughs!