Design of compound libraries based on natural product scaffolds and protein structure similarity clustering (PSSC)

Abstract

Recent advances in structural biology, bioinformatics and combinatorial chemistry have significantly impacted the discovery of small molecules that modulate protein functions. Natural products which have evolved to bind to proteins may serve as biologically validated starting points for the design of focused libraries that might provide protein ligands with enhanced quality and probability. The combined application of natural product derived scaffolds with a new approach that clusters proteins according to structural similarity of their ligand sensing cores provides a new principle for the design and synthesis of such libraries. This article discusses recent advances in the synthesis of natural product inspired compound collections and the application of protein structure similarity clustering for the development of such libraries.

Principles, implementation, and application of biology-oriented synthesis (BIOS)

“…Finally, additional cheminformatic analyses such as protein structure similarity clustering or protein fold topology analyses hold great promise to expand the applicability of BIOS-derived compound libraries, enabling, for example, a prediction of possible protein targets to a given compound collection (Koch et al, 2004;Balamurugan et al, 2005;McArdle and Quinn, 2007). It is to be expected that further development of alternative cheminformatic methods along this line would be of great advantage for chemical biology research.…”

Structure–activity relationships and mechanism of action of antitumor bis 8-hydroxyquinoline substituted benzylamines

“…Privileged substructures from bioactive natural products have played and continue to play an invaluable role in the drug discovery process [1][2][3] The diversification of these heterocyclic compounds using diversity-oriented synthesis (DOS) has been proven to be an essential tool to rapidly discover biologically active small molecules [4][5][6]. Therefore, the development of a concise and efficient strategy leading to skeletal and stereo chemical diversity has gained much attention in scientific communities involved in drug discovery and biomedical research [7].…”

Discovery, Development, and Regulation of Natural Products

“…However, large collections of pure natural products are rare and the quantities of individual compounds that are isolated are typically small. A more recent strategy has been to use natural product scaffolds as templates for creating libraries of semi-synthetic and synthetic analogues [21,28,47]. Rosen et al identified several hundred unique natural products which could serve as starting points in the search for novel leads with particular properties [48].…”