Chemical structure space

In addition to looking for data trends in physical property space using PCA and PLS, trends in chemical structure space can be delineated by viewing nonlinear maps (NLM) of two-dimensional structure descriptors such as Unity Fingerprints or topological atom pairs using tools such as Benchware DataMiner [42]. Two-dimensional NLM plots provide an overview of chemical structure space and biological activity/molecular properties are mapped in a 3rd and/or 4th dimension to look for trends in the dataset. 

The dimensionality of chemical structure space exceeds that of known biological functional space. The dimensionality of biological functional space has increased in recent years due to the discovery of a multitude of genes, largely from the Human Genome Project. This chapter, however, will focus on chemical diversity rather than functional diversity. Quantification of chemical diversity involves two areas first, the predefmition of a chemical space, accomplished by selection of a diversity metric and a compound representation (i.e., molecular descriptors) and second, a rational subset selection, or classification, method dependent on efficient dimensionality reduction. Here, we describe these methods, prerequisites for a definition... 

Principle 3 defines an applicability domain that refers to the response and chemical structure space in which the model makes predictions with a given reliability. Ideally the applicability domain should express the structural, physicochemical, and response space of the model. The chemical structure space can be expressed by information on physicochemical properties and/or structural fragments. The response can be any physicochemical, biological, or environmental effect that is being predicted. 

As outlined 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. ... 

Then there is focussed library synthesis, FLS. In its broadest sense this involves synthesis of a larger number of compounds than TOS, often using solid-phase chemistry (Box 1), but where all the products are still quite similar. FLS allows more exhaustive exploration than TOS of a relatively small volume of biological chemical structure space. Peptide library synthesis can be considered one of the first examples of this category because an underlying polypeptide backbone, which is the same for all members of the library, is elaborated with variable side-chains. Taking its lead from peptides and oligo-nucleotides, much effort has been directed over the last decade towards library synthesis with substrates bound to solid supports, to facilitate... 

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