Substructural environment

One of the most widely used - and successful representations of the constitution, the topology, of a molecule is the HOSE code (Hierarchical Ordered description of the Substructure Environment) [9]. It is an atom-centered code taking into account... 

Atom and bond fragments Substructures (atom groups) Substructure environment Number of carbon atoms Number of rings (In polycyclic compounds) Molecular connectivity (extent of branching)... 

What conclusions can we draw from this body of work. Many of the published studies of bioisosterism, including the majority of those listed in Table 13.1, have involved the gross assumption that the equivalences that are identified are generally applicable, irrespective of the substructural environment or the biological target. 

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. 

The atoms on which the MODSMI transformations are to be applied are identified by a GENIE search that recognises atoms or bonds from their substructural environment. They are highlighted for ALADDIN processing with the GCL command PRINT /BOLDID/ . Because the hit atoms from an ALADDIN geometric test are labelled with the geometric object to which they correspond, MODSMI transformations can be applied to all atoms that are in a particular substructural environment or to only such atoms with a particular... 

Topological Representation and Topology), geometrical, electronic, and physicochemical. Topological de.scriptors are derived directly from the connection table repre.sentation of the structure and include atom and bond counts,. substructure counts, molecular connectivity indices (see Topological Indices), kappa indices, substructure environments, path descriptors, distance-sum connectivity, and molecular symmetry. Substructure-ba.sed descriptors are topological de.scriptors which allow the tailoring of the descriptor set to. specific user-defined substructures contained in the molecules of the data set. 

HOSE = hierarchical ordered description of the substructure environment JCAMP = Joint committee on atomic and molecular physical data net CDF = network common data form NIMRC = National Institute of Materials and Chemical Research. 

Besides structure and substructure searches, Gmclin provides a special search strategy for coordiuation compouuds which is found in no other database the ligand search system, This superior search method gives access to coordination compounds from a completely different point of view it is possible to retrieve all coordination compounds with the same ligand environment, independently of the central atom or the empirical formula of the compound. 

An enhancement of the simple substructure approach is the Fragment Reduced to an Environment that is Limited (FREL) method introduced by Dubois et al. [7] With the FREL method several centers of the molecule are described, including their chemical environment. By taking the elements H, C, N, O, and halogens into account and combining all bond types (single, double, triple, aromatic), the authors found descriptors for 43 different FREL centers that can be used to characterize a molecule. 

However, one of the most successfiil approaches to systematically encoding substructures for NMR spectrum prediction was introduced quite some time ago by Bremser [9]. He used the so-called HOSE (Hierarchical Organization of Spherical Environments) code to describe structures. As mentioned above, the chemical shift value of a carbon atom is basically influenced by the chemical environment of the atom. The HOSE code describes the environment of an atom in several virtual spheres - see Figure 10.2-1. It uses spherical layers (or levels) around the atom to define the chemical environment. The first layer is defined by all the atoms that are one bond away from the central atom, the second layer includes the atoms within the two-bond distance, and so on. This idea can be described as an atom center fragment (ACF) concept, which has been addressed by several other authors in different approaches [19-21]. 

A useful empirical method for the prediction of chemical shifts and coupling constants relies on the information contained in databases of structures with the corresponding NMR data. Large databases with hundred-thousands of chemical shifts are commercially available and are linked to predictive systems, which basically rely on database searching [35], Protons are internally represented by their structural environments, usually their HOSE codes [9]. When a query structure is submitted, a search is performed to find the protons belonging to similar (overlapping) substructures. These are the protons with the same HOSE codes as the protons in the query molecule. The prediction of the chemical shift is calculated as the average chemical shift of the retrieved protons. 

The most specific defined functional groups actually present in the unknown are benzyl, monosubstituted-benzene, X-CH2CH2-X (where the "X" represents any group other than -H or -CH2-), and methyl-ketone. That is, the program would have achieved a perfect score had it reported these substructures and no others. In fact, the program was unable to determine the correct environments of the ketone and -CH2- groups, although it reported only one incorrect substructure. 

Figure 5- Substructures utilized by ADAPT ( ) to generate environment descriptors (from Ref. T).

Canonical correlation analysis was used to relate small subsets of physicochemical parameters to the MDS space. Small subsets were necessary because in canonical correlation analysis, the number of stimuli should be greater than the number of dimensions and physicochemical parameters combined. The analysis revealed that a linear combination of two ADAPT parameters in Table 3 (number of oxygen atoms and chemical environment of substructure (7)) in addition to a concentration variable accounted for 63% of the arrangement of the pyrazine odor space. 

Unclear Magnetic Kesonance Spectroscopy. Bruker s database, designed for use with its spectrophotometers, contains 20,000 13C-nmr and Tl-nmr, as well as a combined nmr-ms database (66). Sadder Laboratories markets a PC-based system that can search its collection of 30,000 13C-nmr spectra by substructure as well as by peak assignments and by full spectrum (64). Other databases include one by Varian and a CD-ROM system containing polymer spectra produced by Tsukuba University, Japan. CSEARCH, a system developed at the University of Vienna by Robien, searches a database of almost 16,000 13C-nmr. Molecular Design Limited (MDL) has adapted the Robien database to be searched in the MACCS and ISIS graphical display and search environment (63). Projects are under way to link the MDL system with the Sadder library and its unique search capabilities. 

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