Scaffold Hopping in Medicinal Chemistry
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.
Identifying and Representing Scaffolds
Markush Structures and Chemical Patents
Scaffold Diversity in Medicinal Chemistry Space
Scaffold Mining of Publicly Available Compound Data
Exploring Virtual Scaffold Spaces
PART II: SCAFFOLD HOPPING METHODS
Similarity-Based Scaffold Hopping Using 2D Fingerprints
CATS for Scaffold-Hopping in Medicinal Chemistry
Feature Point Pharmacophores (FEPOPS)
Three-Dimensional Scaffold Replacement Methods
Spherical Harmonic Molecular Surfaces (ParaSurf and ParaFit)
The XED Forcefield and Spark
Molecular Interaction Fingerprints
PART III: CASE STUDIES
Case Study 1: Scaffold Hopping for T-Type Calcium Channel and Glycine Transporter Type 1 Inhibitors
Case 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
Nathan Brown conducted his doctoral research in Sheffield with Professor Peter Willett focusing on evolutionary algorithms and graph theory. After a two-year Marie Curie Fellowship in Amsterdam in collaboration with Professor Johann Gasteiger in Erlangen, he joined the Novartis Institutes for BioMedical Research in Basel for a three-year Presidential Fellowship in Basel working with Professors Peter Willett and Karl-Heinz Altmann.
His work has led to the pioneering work on multiobjective de novo design in addition to a variety of discoveries and method development in scaffold hopping, bioisosteric identifi cation and replacement, molecular descriptors and statistical modeling. Nathan continues to pursue his research in all aspects of in silico medicinal chemistry.
“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)