Database molecule preparation

Once a database of candidate molecules has been prepared, it may be desirable to select a diverse set of molecules. Diversity algorithms are designed to select sets of molecules in such a way that the chemical space from which they have been extracted is sampled democratically.1291 Molecules are represented in this space using molecular descriptors and dissimilarity between them is quantified using metrics derived from the value of the descriptors. In terms of descriptors that have been used for fragment molecules,... 

High-scoring compounds are then prepared and screened in a biochemical assay. Preparing requires either synthesizing or purchasing a sample of the compound. Sample purchase is normally much faster than synthesis. For this reason, compounds in a virtual screen are often limited to structures that can be purchased from any number of commercial suppliers. Databases of available molecules have been prepared for the sole purpose of assisting virtual screening. 

For each reporter, unambiguous characteristics of the reporter molecule, including the sequence for oligonucleotide based reporters, the source, preparation and database accession number for long reporters, and primers for PCR-based reporters... 

Having identified a natural lead and developed a synthetic route to it, it is then a small step for the chemist to prepare simple analogues of the natural material and investigate their properties. As a result, the chemist then begins to build up a library of chemical structures the properties of which are known as far as the application in question is concerned. This database then enables the pursuit of one of the approaches to rational design of novel molecules, that of design through statistics. 

Database preparation is an important aspect of virtual screening. Molecules must be represented by one or more chemically sensible states and must be formatted appropriately for the virtual screening tool to be used. Relevant considerations include storage format(s), 2D-3D conversion or 3D structure generation, stereochemistry, charge, tautomers, protonation, and conformers. The impact of different database preparation protocols has not been thoroughly evaluated. Limited information in this area indicates that database preparation does impact final screening... 

When preparing conformational ligand databases, we are interested in maximally leveraging the time required for database preparation and the space required for data storage. Since the data can typically be used for multiple target systems, each with different small-molecule requirements, it is most efficient to tag the compounds with a variety of information. This allows the incorporation of physicochemical properties as well as target- or therapeutic area-specific information (see later sections of this chapter), all of which can be used to select subsets of the compounds for specific purposes. 

To conduct a ligand-based virtual screening, at least one active query molecule and a search database are required. Section 3.3 discusses the preparation of search databases and the choice of the queries. 

As mentioned in Section 3.1, a ligand-based virtual screening crucially depends on the knowledge of active query molecules, which can either stem from literature or in-house efforts. In some cases, a wealth of information is available, but not all known active compounds are equally suitable queries for virtual screening. The proper choice of the query and the preparation of both the query and the search database will be discussed in the following section. 

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