Chris Abell

University of Cambridge

Department of Chemistry

Lensfield Road

Cambridge

CB2 1EW

UK

Michelle R. Arkin

University of California, San Francisco

School of Pharmacy

Small Molecule Discovery Center

and

Department of Pharmaceutical Chemistry

UCSF Mission Bay Campus

1700 4th Street

San Francisco

CA 94158

USA

Christoph Arkona

Freie Universität Berlin

Institut für Pharmazie

Königin-Luise-Str. 2 +4

14195 Berlin

Germany

Mahendra Awale

University of Berne

Department of Chemistry and Biochemistry

Freiestrasse 3

3012 Berne

Switzerland

Justin Bower

Cancer Research UK Beatson Institute

Garscube Estate

Switchback Road

Bearsden

Glasgow

G61 1BD, UK

Alexander L. Breeze

AstraZeneca R&D

Discovery Sciences

Alderley Park

Macclesfield

SK10 4TG, UK

and

University of Leeds

Astbury Centre for Structural Molecular Biology

Faculty of Biological Sciences

Leeds

LS2 9JT, UK

Just two decades ago, Stephen Fesik initiated fragment-based ligand design by developing an NMR-based method to search for small, low-affinity ligands in adjacent binding pockets of a protein and to link them to a high-affinity ligand [1]. A broader use of this approach was hindered both by its limitation to relatively small proteins and by a patent application. However, within short time alternative methods emerged, originally based on different NMR techniques, later using protein crystallography. Thus, structure-based design was not any longer restricted to “large” molecules: libraries of much smaller fragment-type compounds were tested experimentally or screened in silico, with the advantage that a small ligand has a much better chance to fit a certain binding site. In further steps, the ligand can grow into the environment of its pocket or can be linked to an adjacent fragment. The only critical step in fragment combination is the search for a linker that combines the fragments in a relaxed, bioactive conformation, optimally stabilizing this favorable conformation.

Ten years later, in 2006, time was already ripe to review the techniques and the accumulated experience in fragment-based ligand design: Wolfgang Jahnke and Daniel Erlanson edited the very first book on this topic [2]. Now, another 10 years later, the discipline has significantly developed and a major number of drug candidates resulted from its use. Thus, we are very grateful that both experts agreed to edit not only a new edition but also a completely new book on fragment-based design. In its introductory section, leading scientists of this area review the role of fragment-based approaches in lead finding and the selection of appropriate targets. Next, an overview on chemical space is provided. The second section discusses library design and various screening techniques, together with a major number of issues that are relevant in fragment-based ligand discovery. The last section presents a significant number of success stories, providing evidence for the broad applicability of fragment-based design in drug research.

As last time, we are very grateful to the editors Daniel Erlanson and Wolfgang Jahnke for assembling such a unique collection of important topics, as well as to all chapter authors for their excellent work. Last but not least we thank the publisher Wiley-VCH, in particular Waltraud Wüst and Frank Weinreich, for their valuable contributions to this project and the entire series.

Düsseldorf
Weisenheim am Sand
Zürich

Raimund Mannhold

Hugo Kubinyi

Gerd Folkers

October 2015

For the great things are not done by impulse, but by a series of small things brought together.

Vincent Van Gogh, 1888

When Wiley-VCH asked us whether we would be willing to edit a new book on fragment-based drug discovery, our first reaction was panic. Editing a book is a daunting task, and having done it once already we knew well what was in store.

Our second reaction was to ask whether a new book was really needed. Since the very first book on fragment-based drug discovery was published by Wiley-VCH in 2006, six more books have appeared, along with dedicated journal issues and dozens of reviews. Was there anything new to say?

Happily, as you will soon discover, the answer is an emphatic yes! This is clearly illustrated by a search for publications containing the phrase “fragment-based drug discovery” in SciFinder®, as seen in the figure.

The past few years have seen a bumper crop of papers on the topic, and given that this search was run in mid-June of 2015 this trend looks set to continue if not accelerate. From its origins as a niche technique, fragment-based approaches have spread throughout the world to organizations large and small and are embraced by biologists, biophysicists, chemists, modelers, and more. More than 30 drugs derived from fragments have entered the clinic (http://practicalfragments.blogspot.com/2015/01/fragments-in-clinic-2015-edition.html), and one (vemurafenib) has already been approved. This book is a comprehensive view of where the field stands – and where it is going.

We would like to thank Wiley-VCH, especially Frank Weinreich and Waltraud Wüst, for encouraging us to undertake this project and patiently working with us through the inevitable but nonetheless frustrating difficulties and delays. We would also like to thank our contributors, all of whom are extraordinarily busy and accomplished scientists. We are thrilled with the response we received to our invitations and with the depth and quality of the chapters. Finally, we would like to thank you for reading. We hope that you will find something useful to apply to your own research: each of our fragmentary efforts advances the great human enterprise of drug discovery.

San Francisco
Basel
October 2015

Daniel A. Erlanson
Wolfgang Jahnke