Substructural analysis, fragment

Ormerod A, Willett P, BawdenD. (1989) Comparison of Fragment Weighting Schemes for Substructural Analysis. Quant. Struet.-Aet. Pel. 8 115-129. 

TABLE 6.22 Substructure analysis data indicating the structures of the fragment ions with their experimentally determined mass, calculated accurate mass, and parts per million error... 

The main drawback of the conventional similarity search concerns an inability to use experimental information on biological activity to adjust similarity measures. This results in an inability to discriminate relevant and non-relevant fragment descriptors used for computing similarity measures. To tackle this problem, Cramer el al. developed substructural analysis, in which each fragment (represented as a bit in a fingerprint) is weighted by taking into account its occurrence in active and in inactive compounds. Subsequently, many similar approaches have been described in the literature. ... 

The substructure list representation can be considered as a one-dimensional representation of a molecule and consists of a list of structured fragments of a molecule the list can only be a partial list of fragments, functional groups, or substituents of interest present in the molecule, thus not requiring a complete knowledge of the molecule structure. The descriptors derived by this representation can be called ID-descriptors and are typically used in - substructural analysis and -> substructure searching. 

Ormerod, A., Willett, P. and Bawden, D. (1989) Comparison of fragment weighting schemes for substructural analysis. Quant. Struct. -Act. Rdat., 8, 115-129. 

CNS activity is a complex process, and remains far from fuUy understood. It is difficult to interpret why certain fragments appear to influence CNS activity. Several compounds with a protonated tertiary amine can pass the blood-brain barrier, although they are not CNS-active. Tertiary amines have a pKa around 7 and can easily be protonated. A comparison of five different approaches, including Bayesian neural network and several other methods described here, revealed that substructural analysis gained so far the best prediction accuracy [38]. 

Third, there is a need to be able to integrate the basic searching facilities with the more sophisticated routines for three-dimensional structure matching that have been described in this review. ° ° ° An obvious related area is the use of three-dimensional structures to derive descriptors for quantitative structure-aaivity relationships. This could be either an extension of the wide use of two-dimensional fragments for substructural analysis stud-ies 8 8i to three-dimensional fragments, or the automatic generation of data for a prediction of potency, e.g., the recent work of Cramer et al. ° ... 

The similarity methods described above are currently being tested on ten small data-sets from the medicinal chemistry literature that have been used previously by Ormerod et aL in studies of fragment weighting schemes for substructural analysis. Each of the data-sets contains between one hundred and two hundred compounds for which both 3-D structural and biological activity data are available. 

The NIST library is available with a new version of the NIST Mass Spectral (MS) Program (v.2.0g) and the enhanced versions of MS Interpreter and AMDIS, the mass spectral interpretation tools with thermodynamics-based interpretation of fragmentation and chemical substructure analysis. The binary format has not changed from the 2002 version, although several new files have been added that associate equivalent compounds and link individual compounds to the RI library. Raw data files are provided in both an SDFile format (structure and data together) as well in earlier formats. The SDFile format holds the chemical structure as a MOLFile and the data in a simple ASCII format. The NIST MS Search Program is also part of many commercial instrumental GC-MS software suites. 

Since the reactive substructure of cA-2-(l,3-butadienyl)cyclopropylidene is contained in the bicyclic carbene 124, there is a possibility that a carbene-carbene rearrangement occurs together with 1,5-carbon migration. Analysis of the probable reaction pathways allows one to conclude that 1,5-C-migration (124 - 132) in the fixed c -l,3-butadienyl fragment of structure 124 is impossible. The 1,3-carbon migration (124 - 130) which takes place instead is mechanistically analogous to the vihylcyclopropylidene-cyclopentylidene... 

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