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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 part describes the most common tools and methods for scaffold hopping, whether topological, shape-based or structure-based. Methods such as CATS, Feature Trees, Feature Point Pharmacophores (FEPOPS), and SkelGen are discussed among many others. 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.
List of contents
PART I: SCAFFOLDS: IDENTIFICATION, REPRESENTATION DIVERSITY AND NAVIGATIONIdentifying and Representing ScaffoldsMarkush Structures and Chemical PatentsScaffold Diversity in Medicinal Chemistry SpaceScaffold Mining of Publicly Available Compound DataExploring Virtual Scaffold SpacesPART II: SCAFFOLD HOPPING METHODSSimilarity-Based Scaffold Hopping Using 2D FingerprintsCATS for Scaffold-Hopping in Medicinal Chemistry Reduced GraphsFeature TreesFeature Point Pharmacophores (FEPOPS)Three-Dimensional Scaffold Replacement MethodsSpherical Harmonic Molecular Surfaces (ParaSurf and ParaFit)The XED Forcefield and SparkMolecular Interaction FingerprintsSkelGenPART III: CASE STUDIESCase Study 1: Scaffold Hopping for T-Type Calcium Channel and Glycine Transporter Type 1 InhibitorsCase Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)Case Study 3: Fragment Hopping to Design Highly Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors
About the author
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.
Hugo Kubinyi gehört seit 1985 der BASF AG an, wo Kombinatorische Chemie, Molecular Modelling und Wirkstoffdesign zu seinen Tätigkeitsfeldern zählten. Sein Spezialgebiet sind Struktur-Wirkungs-Beziehungen und QSAR-Methoden.
Summary
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 part describes the most common tools and methods for scaffold hopping, whether topological, shape-based or structure-based. Methods such as CATS, Feature Trees, Feature Point Pharmacophores (FEPOPS), and SkelGen are discussed among many others. 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.
Report
"This book outlines the key concepts, methods and examples of scaffold hopping in pharmaceutical and related industries. Examples from academia and from industry are fully described, and this book serves as the primary reference to the current state of research in the field." ( ChemMedChem , 1 January 2015)
