Substructure-based approaches

The Rekker approach is still used with revised Z/ systems, e.g., in the software program Z/SYBYL [8]. Over recent decades various other substructure-based approaches have been developed that are mostly implemented and available as computer programs. 

Figure 15.2 Historical progress of ligand structure-based approaches from substructure search to analysis of 3-dimensional molecular interaction fields.

In this chapter, we describe substructure-based logP calculation approaches comprising fragmental and atom-based methods property-based approaches are discussed in Chapter 15. 

Tab. 14.5 Validity check of substructure-based calculation approaches.

In addition to physical properties, substructure-based filters can be applied to reduce further the number of molecules, for instance molecules with undesirable functionality for example, reactive or toxic groups can be removed and molecules with particular features (or atoms) can be actively selected. There may be particular functionality that it is desirable to avoid due to assay format, such as fluorophores in fluorescence-based approaches. Structural features for these inclusion and exclusion criteria can be readily formulated using SMILES-based procedures and this type of substructure-based compound selection technique can also be employed in the generation of focused sets of fragment molecules. 

BgW The BgVV database has been used to develop specific S AR models for predicting skin irritation and corrosion. These models have been incorporated into a decision support system (DSS). The DSS is mainly a rule based approach, the rules being developed are not only based on substructural features but additionally incorporate specific physicochemical properties such as Log P, molecular weight, and aqueous solubility. The rules have been developed and validated on a total of 1508 compounds of which 199 are classified as hazardous. The DSS is designed to predict EU risk phrases. 

Several product-based approaches to library design that do not require full enumeration have been developed. Pickett et al. have described the design of a diverse amide library where diversity is measured in product space. The DIVSEL program is a DBCS method where dissimilarity is measured in three-point pharmacophore space [83]. Initially, 11 amines were selected based on maximum pharmacophore diversity. Then a total of 1100 carboxylic acids were identified following substructure searching. A set of 1100 pharmacophores keys was generated, where each key corresponds to one acid combined with the 11 amines. DIVSEL was used to select 100 acids based on the diversity of the products. The final library was found to cover 85% of the pharmacophores represented by the entire 12,100 virtual libraries. 

The two principal approaches to QSARs comprise the substructure-based methods and the linear free-energy relationship technique (LEER), which... 

This analysis is both an exhaustive index to the database and a highly descriptive summary of the reaction classes in the CASREACT database. This can be equally useful as a learning tool, helping the chemist to discover unexpected relationships. As an index, the analysis offers an alternative and complementary approach to traditional substructure-based reaction... 

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