Biology Oriented Synthesis

The term biology-oriented synthesis (BIOS) [45] has been used to describe the design of compound libraries based on biologically relevant chemical space [46]. The areas in protein structures that participate in productive protein-ligand interactions have been, for the most part, already defined by natural products and drugs. Thus libraries inspired by natural products and other bioactive molecules are expected to have a higher probability of biologically activity than randomly synthesized molecules [47,48]. 

CHAPTER 9 Biology Oriented Synthesis and Diversity Oriented Synthesis in Compound Collection Development 

As ouflined above the chemical structure space accessible to small drug-like molecules is so vast that it cannot be covered by chemical synthesis in a comprehensive and meaningful manner. During evolution nature herself has explored only a tiny fraction of chemical space in the biosynthesis of low molecular weight natural products. The same is true for the evolution of the targets bound and modulated by natural products, for example proteins. It has been estimated that during the evolution of a protein consisting of about 100 amino acids only a tiny fraction of all amino acid combinations could have been biosynthesized. However, in protein evolution, structure is even more conserved than the sequence since similar structures can be formed by very different sequences. Thus the protein structure space explored by nature is limited in size.  

A new approach termed Biology Oriented Synthesis (BIOS) has been developed recently by Waldmann et alf This approach is based on the structural similarity between small bioactive molecules on the one side and their receptors, that is proteins, on the other side as well as on the complementarity of both. BIOS employs compound classes from biologically relevant regions of chemical space, for example natural product or drug space, to select scaffolds as starting points for the design and synthesis of small focused libraries with limited diversity. In this respect BIOS provides a conceptual alternative to other approaches 

These two approaches, the scaffold tree as applied in SCONP as well as PSSC, are introduced and exemplified by selected applications in the following sections. We also demonstrate first applications of BIOS which successfully combine chemistry and biology. 

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S. Basu, B. Ellinger, S. Rizzo, C.l. Deraeve, M. Schurmann, H. Preut, H.-D. Arndt, and H. Waldmann, Biology-oriented synthesis of a natural-product inspired oxepane. Collection yields a small-molecule activator of the Wnt-pathway, Proc. Natl. Acad. Sci. USA., 108 (2011) 6805-6810. 

K, Schwalbe HJ, Vestweber D, Cagna G, Schunk S, Schwarz O, Schiewe H, Waldmann H. Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc. Nat. Acad. Sci. U.S.A. 2006 1003 10606-10611. 

Sohma Y, Kiso Y. Click peptides -chemical biology-oriented synthesis of Alzheimer s disease-related amyloid (> peptide (Afl) analogues based on the O-acyl isopeptide method . Chem-BioChem. 2006 7 1549-1557. 

Diversity oriented synthesis (DOS) Biology oriented synthesis (BIOS)... 

Reis-Correa, I., Noeren-Mueller, A., Ambrosi, H. D., Jakupovic, S., Saxena, K., Schwalbe, H., Kaiser, M., Waldmann, H. Identification of inhibitors for mycobacterial protein tyrosine phosphatase B (MptpB) by biology-oriented synthesis (BIOS). Chem. Asian . 2007,2,1109—1126. 

Mamane, V., Garcia, A. B., Umarye, J. D., Lessmann, X, Sommer, S., Waldmann, H. Stereoselective allylation of aldehydes on solid support and its application in biology-oriented synthesis (BIOS). Tetrahedron 2007,63,5754-5767. 

But progress continues to be made, and more and more biologically active compounds continue to come out of DOS libraries. Another approach to the generation of synthetic compounds more closely resembling natural products, evolutionarily selected chemical structures encoding the properties required for binding to proteins, called Biology-Oriented Synthesis BIOS) was developed by Dr Herbert Waldmann at the Max Planck Institute. 

In this chapter, we address two complimentary approaches to componnd collection development namely, Diversity Oriented Synthesis (DOS) and Biology Oriented Synthesis (BIOS). For additional, very well-validated approaches snch as fragment-based design and the application of in silico methods to develop compound libraries the reader is referred to different chapters in this book and to authoritative reviews. " ... 

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