Databases identifying biological activity

A third and slightly older method available is the UNITY package from Tripos Inc. This also relies on the user to identify pharmacophore features and spatial arrangement. When multiple compounds and biological activity is known, this can be used to focus on a limited number of features or to exclude specific volume from the molecule. The compounds in the database are then compared to the query... 

The concept of scaffold hopping invokes the use of computational tools that when given a reference structure can propose a different structure likely to have similar biological properties. A comprehensive scaffold database to serve for scaffold-hopping purposes has been created and is publicly available [59]. The database was based on the analysis of more than 4 million compounds to identify 241,824 unique scaffolds. In addition to the scaffold structure, the database contains information about the original molecule and its biological activity as well as its calculated physicochemical properties. 

These databases are a rich source of information, yet they do not capture an element of interest, namely the biological endpoint there is no searchable field to identify, in a quantitative manner, what is the target-related activity of a particular compound. Such information is important if one considers that (a) not all chemotypes indexed in patent databases are indeed active - some are just patent claims with no factual basis and that (b) not aU chemotypes disclosed as active are equally active, or selective for that matter, on the target of choice. Furthermore, should one decide to pursue a certain interaction hotspot in a given ligand-receptor structure (assuming good structure-activity models are available), it would be very convenient to mine structure-activity databases for similar chemotypes to use as potential bioisosteric replacements. 

Substructure searching has also been coupled with statistical analysis to identify molecular fragments that are associated with biological activity of test compounds (Roberts et al. 2000). For example, substructures can be taken from series of active compounds and their frequency of occurrence in compound databases can be determined. Then the statistical significance of this frequency of occurrence in active molecules and database compounds can be compared which might indicate whether or not a specific structural motif could be responsible for a given biological activity. 

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