This first systematic treatment of the concept and practice of scaffold hopping shows the tricks of the trade and provides invaluable guidance for the reader's own projects. The first section serves as an introduction to the topic by describing the concept of scaffolds, their discovery, diversity and representation, and their importance for finding new chemical entities. The following parts contain a general description as well as case studies of the most common tools and methods for scaffold hopping, whether topological, shape-based or structure-based. The final part contains three fully documented real-world examples of successful drug development projects by scaffold hopping that illustrate the benefits of the approach for medicinal chemistry. While most of the case studies are taken from medicinal chemistry, chemical and structural biologists will also benefit greatly from the insights presented here.
Nathan Brown is the Head of the In Silico Medicinal Chemistry Group within the Cancer Therapeutics Unit at The Institute of Cancer Research in Sutton (UK). He conducted his doctoral research with Prof. Peter Willett at the University of Sheffield, before moving to Amsterdam (The Netherlands) for a Marie Curie fellowship in collaboration with Prof. Johann Gasteiger. This was followed by a Presidential fellowship at Novartis in Basel (Switzerland). Dr. Brown has published in a wide range of areas of computational chemistry, most notably de novo design and molecular descriptors.
Table of Contents
INTRODUCTION TO SCAFFOLD HOPPING Identifying and representing scaffolds Markush structures and chemical patents Diversity of scaffolds from natural products Scaffold diversity in medicinal chemistry space Exploring virtual scaffold spaces
TOPOLOGICAL METHODS FOR SCAFFOLD HOPPING CATS vectors Reduced graphs Feature trees (FTrees) Extended connectivity fingerprints (ECFP) Maximum common substructure determination in MedChem Studio
SHAPE-BASED METHODS FOR SCAFFOLD HOPPING Radial distribution function codes Rapid overlay of chemical structures (ROCS) FEPOPS ParaFit XED Forcefields and Fieldstere Ultrafast shape recognition (USR)
PHARMACOPHORE AND STRUCTURE-BASED METHODS SkelGen Molecular interaction fingerprints ReCore SHOP
SCAFFOLD HOPPING CASE STUDIES JAK2 inhibitors mGluR5 inhibitors Phosphatase inhibitors