The year is done, and the darkness
Falls from the wings of Night.
Significant events included the venerable CHI FBDD meeting in San Diego, the NovAliX Biophysics conference in Strasbourg, and the first-ever fragment conference in Shanghai. We discussed a special issue of Essays in Biochemistry devoted to structure-based drug design, and Teddy came out of retirement to provide an entertaining summary of his experience putting together a book on biophysics in drug discovery - well worth reading if you're ever tempted to edit one yourself.
As in years past, several reviews were devoted to the broad topic of FBDD. Below, I’ll outline the general reviews, followed by those focusing on particular targets, techniques, and other topics.
György Keserű (Hungarian Academy of Sciences) and Mike Hann (GlaxoSmithKline) ask “what is the future for fragment-based drug discovery?” in Fut. Med. Chem. After a concise summary of the topic, they answer that it “includes target discovery and validation, the development of chemical biology probes, pharmacological tools and more importantly drug-like compounds.” In other words, the future looks bright.
FBDD is more comprehensively covered by Ben Davis and Stephen Roughley (Vernalis) in Ann. Reports Med. Chem. This is a complete, self-contained guide to the field, covering everything from history, theory, fragment library design, and fragment-to-lead approaches. It is ideal for a newcomer, but there are enough insights throughout that it makes a rewarding read for experts too.
And rounding out general reviews, Christopher Johnson (Astex) and collaborators examined all 28 successful fragment-to-lead programs published in 2016, defined as at least a 100-fold improvement in affinity to a 2 µM or better compound. This is a sequel to our analysis of the 2015 literature, also published in J. Med. Chem., and many of the trends are similar. Interestingly, many leads maintained high ligand efficiencies, and there was no correlation between the “shapeliness” (deviation from planarity) of fragments and that of the resulting leads. Consistent with our recent poll on the importance of structural information, 25 of the 28 examples used crystallography at some point.
More than 30% of enzymes are metalloenzymes, yet these are targeted by fewer than 70 FDA-approved drugs. One of the first published examples of FBDD involved a metalloenzyme, but most efforts have been focused on a limited set of metal-binding pharmacophores, such as hydroxamic acids. Seth Cohen (University of California, San Diego) has been steadily building libraries of metallophilic fragments, and in Acc. Chem. Res. he describes how this approach can lead to new classes of inhibitors.
Protein-protein interaction inhibitors are another underrepresented class of drugs, though one approved FBDD-derived molecule falls into this category. In Methods, Daisuke Kihara and collaborators at Purdue University look at in silico methods to discover PPI inhibitors, including fragment-based approaches.
Unlike PPIs, kinases have been highly successful drug targets. We recently highlighted one review of cyclin-dependent kinases (CDKs), and in Eur. J. Med. Chem. Marco Tutone and Anna Maria Almerico (Università di Palermo) provide another. Although the main focus is on in silico methods, there is a section on FBDD.
As noted above, X-ray crystallography has played a role in most successful fragment to lead programs. In the open-access journal IUCrJ, Sir Tom Blundell (University of Cambridge) provides an engaging and personal view of protein crystallography, a field in which he has played a starring role, starting with his early involvement in determining the crystal structure of insulin. He also notes that the interchange of ideas and techniques between academia and industry has long been a crucial driver of advances.
NMR was the first practical method used for FBDD, so it is not surprising that there are several reviews on the topic. In Arch. Biochem. Biophys., Michael Reily and colleagues at Bristol-Myers Squibb provide a detailed overview of NMR in drug design. This covers not just the ligand- and protein-detection methods often used in fragment screening, but also more intensive techniques to characterize protein-ligand interactions.
Artifacts are a fact of life in both FBDD and HTS, and it is always important to recognize these early. In J. Med. Chem. Anamarija Zega (University of Ljubljana) discusses how NMR can help. This includes methods to detect aggregators and covalent modifiers. Of course, NMR methods can introduce their own artifacts, and these are also covered.
Speaking of artifacts, PAINS are responsible for quite a few. The term “PAINS” has also been somewhat controversial, and in a new paper in ACS Chem. Biol. Jonathan Baell (Monash University) and J. Willem Nissink (AstraZeneca) examine the “utility and limitations” of the term Jonathan coined seven years ago. As they acknowledge, the PAINS filters were derived from just 100,000 compounds run in a limited set of assays. This means that not every bad actor will be recognized by PAINS filters, and some compounds that are may only be PAINful in certain assay formats. Like Lipinski’s rule of 5, it is important to recognize the limits of applicability. As the authors note, “the key is to remain evidence-based.”
Another sometimes controversial topic is ligand efficiency and associated metrics, the subject of an analysis in Expert Opin. Drug Disc. by Giovanni Lentini and collaborators at the University of Bari Aldo Moro. This includes extensive tables of rules and metrics, both common and obscure. The authors note that, while metrics can be useful, it is important not to use them as a “magic box.” As they quote William Blake, “to generalize is to be an idiot.”
Shawn Johnstone and Jeffrey Albert (IntelliSyn Pharma) discuss pharmacological property optimization for allosteric ligands in a review in Bioorg. Med. Chem. Lett. As we recently noted, fragments are particularly suited for discovering allosteric sites, and this paper discusses how to characterize these.
Finally, Jörg Rademann and collaborators at Freie Universität Berlin discuss protein-templated fragment ligations in Angew. Chem. Int. Ed. Earlier this year we highlighted some of his work, and this review provides a thorough analysis of both reversible and irreversible approaches, with good discussions of detection methods, chemistries, and case studies.
That’s it for the year. Thanks for reading, and especially for commenting.
And may 2018 be filled with music, and light.