Biological space starting points

Brohm, D., Metzger, S., Bhargava, A., Muller, O., Lieb, F., and Waldmann, H. (2002) Natural products are biologically validated starting points in structural space for compound library development solid phase synthesis of dysidiolide-derived phosphatase inhibitors. Angew. Chem. Int. Ed. 41, 307-311. 

In developing new concepts and logics for meeting this demand the central and crucial tasks are to identify compound classes that represent already biologically validated starting points in structural space, to find a synthetic access to them that is amenable to combinatorial variation and to design and synthesize combinatorial libraries centered on the identified underlying structural framework of these compound classes. 

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... 

Aims to achieve maximum diversity around a core structure in chemical space selected because of its chemical accessibility. DOS also alms at diversity in the core structure if possible. Alms to achieve focused diversity around a starting point in the biologically relevant chemical space. These starting points are often natural product core structures. 

Fig. 15.1-3 Schematic visualization of the various concepts to address chemical and biological space (shaded areas) in drug discovery. Medicinal chemistry focused on compound series (red dots) that had shown activity in pharmacological assays and compound optimization was driven by a tight feedback from biological experiments, leading to a focused nonarrayed addressing of chemical space. The combinatorial promise was to systemically explore the chemical space with diverse arrays of compounds (blue dots) to find the suitable starting points. Analysis of combinatorial chemistry libraries showed their limited...

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