Methods in Enzymology: Fragment-Based Drug Design

In addition to dozens of reviews on fragment-based drug discovery, entire books have been published, the first in 2006 and the second in 2008. Now a third has joined the list: Volume 493 of the venerable Methods in Enzymology series, edited by Lawrence Kuo at Johnson & Johnson, is titled Fragment-Based Drug Discovery: Tools, Practical Approaches, and Examples. With 21 chapters and roughly 600 pages, it is a comprehensive addition to the field. Whether you’re just starting out in the field of fragments or already an expert, this is an invaluable resource.

As the subtitle suggests, the book is divided into three sections. The first, Tools, is the shortest, consisting of just 6 chapters. Chapter 1, by Brett Tounge and Michael Parker, describes how they assembled a 900 fragment library at Johnson & Johnson for use in crystallography-based screening. Chapter 2, by Gaetano Montelione and colleagues, discusses the high-throughput protein preparation approach that the Northeast Structural Genomics Consortium has taken, including advice on what to do when problems arise. The next two chapters are devoted to crystallography: Jark Böttcher and colleagues from Proteros Biostructures provide a general overview including practical tips in Chapter 3, while Doug Davies and colleagues from Emerald BioStructures analyze the results of 18 in-house campaigns to try to draw general conclusions of why some targets are more successful than others in Chapter 4. On the subject of difficult targets, Chapter 5 is devoted to GPCRs, specifically the stabilized versions being generated by Miles Congreve and coworkers at Hepatares Therapeutics and analyzed by SPR and TINS NMR in collaboration with researchers at the University of Utah and ZoBio. Finishing out this section, Renee DesJarlais of Johnson & Johnson provides an overview and practical tips for applying computational approaches to FBDD.

The second section, Practical Approaches, begins with a chapter by Lawrence Kuo on how to ensure that hits from fragment screens will be distinct from those coming out of HTS. Chapter 8, by Tony Gianetti at Genentech, is a valuable and comprehensive tutorial on using SPR for fragment screening. The next two chapters are devoted to NMR: Chapter 9, by Christopher Lepre at Vertex, discusses such practicalities as library preparation and NMR screening conditions, while Chapter 10, by Joshua Ziarek and colleagues at the Medical College of Wisconsin provides more detail on specific NMR techniques. The following two chapters discuss a couple less common techniques. Chapter 11, by James Kranz at GlaxoSmithKline and Celine Schalk-Hihi at Johnson & Johnson, gives an excellent description of the protein thermal shift technique for identifying and characterizing fragments, complete with all the mathematics. And Chapter 12, by Lars Neumann and colleagues at Proteros Biostructures, describes the reporter displacement assay and its use to select for fragments with desirable kinetic and thermodynamic profiles. In Chapter 13, John Spurlino of Johnson & Johnson describes crystallography-based fragment screening and advancement without collecting affinity data; this was recently discussed here, but the chapter provides additional details and examples. Finally, the last chapter in this section, by Zenon Konteatis and colleagues at Ansaris, discusses the incorporation of protein flexibility into computational fragment-based screening.

The last section, Examples, opens with a chapter by Masaya Orita and colleagues at Astellas that covers ligand efficiency and related indices and an overview of strategies to advance fragments, with a particular emphasis on “anchor-based drug discovery.” Chapter 16, by James Lanter and colleagues at Johnson & Johnson, emphasizes the importance of engaging medicinal chemists in fragment projects from an early stage. In Chapter 17, Hugh Eaton and Daniel Wyss at Merck describe using NMR in FBDD both in general terms and with respect to their BACE1 program, which has entered clinical trials. Chapter 18, by Till Maurer at Genentech, is also devoted to NMR, focusing on the specific steps involved. Chapter 19, by Marta Abad and colleagues at Johnson & Johnson, returns to crystallography, further discussing the electron-density guided FBDD approach in the context of the target ketohexokinase. In Chapter 20, Rod Hubbard and James Murray discuss a decade of fragment work at Vernalis, integrating many of the techniques discussed in the rest of the volume (as well as a few new ones!) and providing a valuable discussion on why orthogonal biophysical fragment-finding methods are necessary. The book closes with a chapter by Darren Begley and colleagues at Emerald BioStructures and collaborators at the University of Washington on a structural genomics initiative to use crystallography-guided methods to tackle proteins important in infectious diseases.

Although each of these chapters can be downloaded individually, it is well worth getting a copy of the book itself. Like other members of the series, it is beautifully put together. Having all the papers in one place is extremely convenient, and simply paging through the volume is bound to generate new ideas.