Structure searching chemical diversity

The distribution of Tanimoto indices for randomly selected (or all) pairs of structures characterizes the diversity of a chemical structure database (Demuth et al. 2004 Scsibrany et al. 2003). For structure similarity searches, a number of other similarity measures have been suggested (Gasteiger and Engel 2003 Willett 1987). 

To demonstrate the use of binary substructure descriptors and Tanimoto indices for cluster analysis of chemical structures we consider the 20 standard amino acids (Figure 6.3) and characterize each molecular structure by eight binary variables describing presence/absence of eight substructures (Figure 6.4). Note that in most practical applications—for instance, evaluation of results from searches in structure databases—more diverse molecular structures have to be handled and usually several hundred different substructures are considered. Table 6.1 contains the binary substructure descriptors (variables) with value 0 if the substructure is absent and 1 if the substructure is present in the amino acid these numbers form the A-matrix. Binary substructure descriptors have been calculated by the software SubMat (Scsibrany and Varmuza 2004), which requires as input the molecular structures in one file and the substructures in another file, all structures are in Molfile format (Gasteiger and Engel 2003) output is an ASCII file with the binary descriptors. 

The concept of molecular dissimilarity is introduced, and shown to be a powerful complement to the well-established notion of molecular similarity. It provides a quantitative assessment of structural variation and diversity. Apphcations within chemical information systems are discussed. These include ranking of search output, selection of representative sets of structures, file screening, data analysis, and creativity stimulation. 

Unknown I. Generate 3D structures, perCnm chemical similarity and diversity, apply combinatorial chemistry 11. Find ligands or ligand fragments to fill receptor sites, de novo design, receptor-based 3D searching... 

Diversity of Chemical Libraries Graph Theory in Chemistry Markush Structure Searching in Patents Nomenclature Searching Ring Perception Shape Analysis... 

Even in this fiiirly diverse data set of structures, the dopamine and benzodiazepine agonists could be separated quite well only two neurons had collisions between these two types ol compounds. Even more importantly, however, we now know in which chemical space one would have to search For new lead structures for dopamine or for benzodiazepine agonists. 

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

Chemical Information, Irvine CA Tripos, Inc. St. Louis MO), similarity searching can be carried out around a well-defined compound class using local descriptors such as atom pairs [46, 47] or topomeric shape [48, 49]. Also, ligand-based pharmacophore searches are able to identify follow-up compounds that are less obvious and more diverse than similarity searches [30, 50-54]. The problem with the latter methods is defining the molecular shape or pharmacophore specifically enough to be useful when there are few hits within a compound class and they cannot be reliably aligned (as is often the case for NMR hits in the absence of detailed structural information). 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

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