Brown N. (Ed.) Scaffold Hopping in Medicinal Chemistry

Wiley-VCH, 2014. — 326 p. — ISBN: 9783527333646In 1999, Gisbert Schneider coined the term “scaffold hopping” for a systematic approach to modify the molecular skeleton of a lead structure. Whereas in bioisosteric replacement atoms or small groups are substituted by other ones with identical or at least similar stereoelectronic features, scaffold hopping exchanges the central part of a molecule by a molecular frame of similar shape and pharmacophoric pattern. Correspondingly, scaffold hopping may be considered as an extension of bioisosteric replacement. In this manner, it provides a conceptual and practical route for generating new chemistry and lead series with higher efficacy, better or modified selectivity, and/or improved pharmacokinetic properties, based on known active principles.
As often in science, this approach is also not completely new. The modification or exchange of a molecular scaffold was already applied in the chemical variation of morphine, quinine, some steroid hormones (e.g., estradiol), and b-blockers, to list only a few examples. Looking at naturally occurring b-lactams, that is, the penicillins, cephalosporins, and monobactams, we see tha also nature some times uses this principle. Like in “fragment-based design,” where a breakthrough came only after the description of the advantages of this method, the definition “scaffold hopping” appealed medicinal chemists to use this strategy – and fueled its systematic application in lead structure search and optimization. Marketed analogs of celecoxib (Celebrex 1 ), sildenafil (Viagra 1 ), and several kinase inhibitors are recent examples of drugs and clinical candidates resulting from this approach.Scaffolds: Identification, Representation Diversity, and Navigation
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
Scaffold-Hopping Methods
Similarity-Based Scaffold Hopping Using 2D Fingerprints
CATS for Scaffold Hopping in Medicinal Chemistry
Reduced Graphs
Feature Trees
Feature Point Pharmacophores (FEPOPS)
Three-Dimensional Scaffold Replacement Methods
Spherical Harmonic Molecular Surfaces (ParaSurf and ParaFit)
The XED Force Field and Spark
Molecular Interaction Fingerprints
SkelGen
Case Studies
Scaffold Hopping for T-Type Calcium Channel and Glycine Transporter Type 1 Inhibitors
Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)
Fragment Hopping to Design Highly Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors