Closed Substructure Search

EXA (exact) search retrieves the input structure and its stereoisomers, homopolymers, ions, radicals, and isotopically labeled compounds. FAM (family) search retrieves the same structures as EXA, plus multicomponent compounds, copolymers, addition compounds, mixtures, and salts. SSS (substructure) search uses a range of possible substituents and bonds in the input structure. CSS (closed substructure) search is a more restrictive... 

Closed Substructure Search (CSS) is a restricted substructure search. It can only be executed by special commands (Sect. 7.2.3.4), which allow substitution at certain positions, as shown in Fig. 101 piceol in or Ao-position. 

Fig. 101. Example for a compound found by Closed Substructure Search for piceol...

A cost-free Sample Search (SAM) should precede each Closed Substructure Search und Substructure Search. A Sample Structure Search is carried out in 5% of the entire data material in order to see whether the generated search profile is likely to be successful, and whether it remains within the capacities imposed by the data system. The Registry File provides the following capacities (Table 8) ... 

The CONNECT command enables inclusion of non-hydrogen atoms at certain positions. This command is suited for a Closed Substructure Search (Sect. 7.2.1). 

In the first instance, we wanted to find close analogues of the reported hit. Such compounds would probably not make ideal chemical starting points because they are too close to the intellectual property space of the reference compound. In this case, it was of value to understand the S AR of a new target and provide active compounds to help with assay validation. To perform these searches, we used 2D fingerprints complemented with substructure searches. The substructure search is still a valuable tool in this regard as it ensures all available compounds with the specific scaffold or chemotype are identified and screened. This satisfies the medicinal chemistry aim of mapping the SAR around chemotypes. 

If measured values are not available for the chemical of interest, a substructure search should be conducted to attempt to identify a close structural analog which has a measured value. Several options are available, a few of which allow the rapid identification of an analog with measured values. For example, there are free databases on the internet that are substructure searchable. ChemlDp/us (Table 1) is substructure searchable for all of the >6000 chemicals that are in the Hazardous Substances Data Bank (HSDB) as well as the 269 000 structures that are in the ChemlDp/us file. ChemS (Table 1) can simultaneously substructure search the 20 000 chemicals in the four files of the Environmental Fate Data Base (EFDB) [4,5]. 

Below you will find some commands providing a higher output of results for a closed structure search as well as a reduction of results during a substructure search. 

During a search for an exact closed substructure, substitutions are not allowed and thus automatically all atoms are saturated by hydrogen. In a substructure search this is somewhat different. The command HCOUNT (HCO) permits enter the number of H atoms which attach at particular atoms of the structure (Sect. 7.2.7). If HCOUNT is undefined, an arbitrary number of H atoms for each node is allowed, including zero. During a CSS search HCOUNTS may be changed in order to place substitutions at certain positions. 

Unlike the Registry File, which contains single, exactly defined compounds, MARPAT provides numerous compounds under a single structure. Since only generic structures are contained in MARPAT, Exact (EXA) and Family Searches (FAM) cannot be executed - it is only possible to conduct Closed Structure Searches (CSS) and Substructure Searches (SSS) (Sect. 7.2.1). 

An important distinaion between ALADDIN and the other programs described in this section is that the user specifies at the time of the search the substructural environment of the atoms and the definition of the geometric objects. This is one key to its flexibility. Another distinction is its close tie to molecular graphics with not only the three-dimensional structure, but also the hit atoms identified for the graphics program. A final distinction is that it has provisions for automatically generating both the two-dimensional and three-dimensional structures of molecules proposed for synthesis. 

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