Chemical space biologically relevant

The challenge in the synthesis of chemical libraries is the vast number of different, potentially drug-like small molecules which is estimated to be as high as 1060. As all of these molecules can never be synthesized and tested, it is essential to define criteria for the composition of libraries spanning the biologically relevant areas of the chemical space most efficiently. An important criterion of a compound library is its chemical diversity, a term describing the similarity or dissimilarity of all library components. Thus, chemical diversity expresses how well a library represents all theoretical possibilities within the chemical property space. A library with low... 

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]. 

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. 

KochMA, SchuffenhauerA, ScheckM, etfl/. (2005) Charting biologically relevant chemical space A structural classification of natural products (SCONP). Proc. Natl. Acad. Set. 102 11111-11211. 

The National Institute of Justice has put together multivolume compendiums of instrumentation relevant to chemical and biological weapons detection. However, none of these books contains a critical review of the effectiveness of the technologies. One instrument included in the publication is a portable, handheld, ion mobility spectrometry chemical agent monitor with moderate to high selectivity, but only when used in open spaces, far from vapor sources such as smoke, cleaning compounds, and fumes. This would seem to make it useless in the battlefield. Another listed chemical agent monitor has a below 5% false positive rate. With one in 20 false positives, no one could reasonably act upon an alarm. 

There are two major classes of libraries for drug discovery diverse libraries for lead discovery and focused libraries for lead optimization. Lead discovery libraries emphasize diversity while lead optimization libraries prefer similar compounds. The purpose of lead discovery libraries is to find lead matter and to provide potential active compounds for further optimization. Without any prior knowledge about the active compounds for a given target, it is reasonable to start with a library of enough chemical space coverage to demarcate the biologically relevant chemical... 

Solid-phase synthesis techniques applied either in a parallel fashion in automated synthesis or in split-pool-synthesis enable the rapid production of compound libraries containing thousands of members. But the original expectation that new hits will be discovered solely by the creation of a large quantity of library members was not fulfilled. Some of the libraries contained hardly any hit, because the underlying structures therein were not biologically relevant. Thus an old question returned Where in the almost indefinite space of thinkable chemical compounds are the structures which are of biological relevance [2] ... 

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. 

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. 

---