Recent Advances in Scaffold Hopping

Abstract

Scaffold hopping refers to the computer-aided search for active compounds containing different core structures, which is a topic of high interest in medicinal chemistry. Herein foundations and caveats of scaffold hopping approaches are discussed and recent methodological developments analyzed. Despite the conceptual prevalence of pharmacophore methods for scaffold hopping, a variety of computational approaches have been successfully applied. In recent years, scaffold hopping calculations are increasingly carried out at the level of scaffolds rather than compounds, and scaffold queries increasingly abstract from chemical structures. In addition, relationships between compounds, scaffolds, and biological activities are beginning to be globally explored, beyond individual applications. Going forward, computational scaffold hopping is thought to benefit from the consideration of new scaffold concepts and the development of methods capable of guiding search calculations toward scaffolds that are likely to represent potent compounds.

Scaffold hopping via ANCHOR.QUERY: β-lactams as potent p53-MDM2 antagonists

“…It allows not only qualitatively evaluating the fact of interaction, but also to semi quantitatively estimating the binding affinity. For this NMR experiment, the uniformly 15 N-labeled MDM2 was titrated with increasing concentration of the evaluated compound and 1 H- 1 5N HMQC spectra were recorded after each new portion of the compound has been added. In the course of titration, the shifts of the cross-peaks assigned to the amino acid affected by binding of small molecule, e.g.…”

“…1,2 Scaffold hopping can yield improved PKPD properties, affinity and selectivity, or intellectual property. We have recently introduced the pharmacophore-based virtual screening platform ANCHOR.QUERY which allows for the fast and efficient screening of very large chemical libraries based on multicomponent reaction chemistries (MCRs).…”

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

“…The discoveries of interleukin‐converting enzyme inhibitors and thrombin inhibitors are successful examples of peptide mimicry. The principal computational approaches for scaffold hopping include shape searching, pharmacophore searching, similarity searching, and ML . For example, shape searching has been successfully used to discover a novel scaffold for small‐molecule inhibitors of an antibacterial target, and pharmacophore searching has been used to identify indolyl‐pyrrolone as a new scaffold for Pim1 inhibitors …”

InterLig: a fast and accurate software for ligand-based virtual screening

“…LBVS methods are based on the assumption that structurally similar compounds have a higher chance of binding to the same receptor [2]. The structural similarity can be calculated by comparing 2D fingerprints of compounds or by more accurate 3D structural alignments [11,5] that also allow scaffold hopping [6,10] and provide starting points for 3D docking.…”