Biology space

A consideration of whether or not a compound fits into the chemical and biological space of the model should be made by the model user. 

In this chapter, the full BioPrint approach is described, as available from Cerep in terms of both the data set and the ability to have new compounds profiled and the results provided in the context of the BioPrint data set, including the known in vivo side effects of near neighbors in this biological space (see Section 2.5). The results for the differentiation of hit/lead compounds (see Section 2.3.2.1) sometimes use a subset of the 70-100 pharmacological assays that provide the maximum signal. Usually a decision on future work prioritization could be clearly made from the data from these subsets, saving time and money. For key reference/tool compounds, a full profile was used and is recommended to be used, as unexpected off-target activities may be found that cannot usually be predicted. 

One of the main problems for the annotation and classification of the biological space is the lack of a standard scheme for all protein families. Even within families, different classification schemes coexist and are being used by different research communities. This aspect hampers enormously any chemogenomic initiative aimed at integrating chemical and biological spaces with novel computational techniques. The following provides an overview of the classification schemes currently in use for the main therapeutically relevant protein families. 

They do, however, have the limitation that they quantify diversity in chemical space, whereas the principal rationale for molecular diversity methods is to maximize diversity in biological space (35), and we hence focus here on indices that take account of biological activity. 

Nettles, J.H., Jenkins, J.L., Bender, A., Deng, Z., Davies, J.W. and Click, M. (2006) Bridging chemical and biological space Target Pishing using 2D and 3D molecular descriptors. Journal of Medicinal Chemistry, 49 (23), 6802-6810. 

I wish to ask about the concept of a unit of length in a biological cell. My concern is with the numerical value to be used for the diffusion coefficient. Most of biological space is heavily organized even in a single cell, and therefore a diffusion constant is not a simple property. To put my question simply, it is easiest, however, to consider enzyme sites that are otherwise identical in two situations (1) with water between them, (2) with a biological membrane between them. Is it not the case that the unit of length is quite different, for the diffusion in (1) is virtually free diffusion whereas in (2) the diffusion is constrained most probably as a series of activated hops ... 

Fig. 23 Bridging biological space. The overlap of epothilone B (cyan carbons) and PTX (green carbons) models derived from EC reveal shared anchors between the exchangeable nucleotide site through H227 and the truncated B9-B10 loop of the beta tubulin site. Perhaps rigidifying this vector across the site is of greater importance to the MT stabilizing effect than picking up interactions within the deep hydrophobic pocket...

In the context of drug discovery, the fraction of chemical space that is relevant to biological space, which is called biologically relevant chemical space , is of prime importance and is significantly smaller than chemical space. It appears that the simplest living organisms can function and survive with just a few hundred different types of molecules. 

Significantly, natural products cover biological space not covered by synthetic drugs, for example ... 

Directly related to the similarity-searching methods are cheminformatics methods that try to align the chemical and biological spaces based on mapping procedures. 

We performed a combined 2D and 3D analysis of chemical and biological space to identify ion channel privileged chemotypes. The 2D approach was based on a collection of biologically active compounds and consisted mainly of similarity and substructure searching and of analysis of common frameworks and fragments. Our 3D approach relied on multiple ion channel pharmacophores and homology models, which were used for virtual screening. 

Haggarty S. J. (2005) The principle of complementarity chemical versus biological space. Current Opinion in Chemical Biology, 9, 296-303. 

Figure 1 Representation of some of the interfaces between biology and chemistry space (a) the continuum of chemistry space continuum with representative regions of specific biological activity highlighted (b) large combinatorial libraries seek to cover as much space as possible across several biological families but with one core scaffold (c) smaller focused libraries, shown as the small blue cubes, are designed with relevant biological targets in mind and(d) libraries that do not overlap with relevant biological space are undesirable...

The success of both target-based and phenotype-based methods relies heavily on the qualities of the chemical libraries used. Although combinatorial technologies allow the synthesis of a large number of molecules with immense structural diversity, it is impossible to saturate the chemical space, which has been estimated to contain more than 10 molecules (8). Because biological space interacts with only a fraction of chemical space, synthetic attempts to increase randomly the molecular... 

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