Bioactive chemical space

Total BioactIve Chemical Space of hERG Channel Blockers... 

Jacoby E, Mozzarelli A (2009) Chemogenomic strategies to expand the bioactive chemical space. Curr Med Chem 16 4374- 381... 

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]. 

In this case, identical areas of chemical space are assayed against the whole target set and no additional artificial dataset bias is introduced into the final models. However, this still does not address the question of whether the bioactivity models employed to predict targets (or off-targets) is able to predict the bioactivity spectrum of a particular compound this depends on whether the new compound is closer to the area covered by experiment, or further away from it. 

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... 

S., Hofmann, B., Wetzel, S., Schuffenhauer, A., Erd, P., Oprea, T.I., Steinhilber, D., Brunsveld, L., Rauh, D and Waldmann, H. (2009) Bioactivity-guided mapping and navigation of chemical space. Nature Chemical Biolc, 5, 585-592. 

Research projects in pharmaceutical industry that are in an early phase need bioactive chemotypes as potential lead structures for optimization. Hits with a medium or even weak activity can serve as leads if the overall profile looks attractive. HTS of the in-house compound libraries is the most common source of these lead structures. If information about the 3D structure of the target and/or about bioactive ligand(s) is available, virtual screening can be used to add further active chemotypes either from the existing compounds, for example, from vendor catalogues, or from the virtual chemical space, for example, from virtual combinatorial libraries. Virtual screening can also be used to select a subset from the in-house screening collection if a full HTS is not possible due to cost or time limitations. 

Figure 6.26 Principal component analysis of chemical space properties for groups of compounds categorized as drugs, bioactives, natural products, fragments, diversity oriented synthesis (DOS) and Rule-of-Five. Numbered compounds representative of the various categories are given in the reference. (Reprinted with permission from Shelat, A. A., Guy, R.K. The interdependence between screening methods and screening libraries. Curr. Opin. Chem. Biol. 2007, 11, 244-251, copyright 2007, Elsevier.)...

Figure 1.2 Structural Classification of Natural Products (SCONP) The molecular scaffolds (ring systems) derived from natural products arranged into hierarchical clusters. (From Bon, R. S. and Waldmann, H., 2010, Bioactivity-Guided Navigation of Chemical Space, Acc. Chem. Res., 43(8) 1103-14.)...

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