Structure databases search techniques

Bures, M. G., Searching Techniques for Databases of Three-Dimensional Chemical Structures, 21, 467. 

Searching Techniques for Databases of Three-Dimensional Chemical Structures... 

Willett, P. (2005) Searching techniques for databases of two- and three-dimensional structures./ourna( of Medicinal Chemistry, 48 (13), 4183-4199. 

M. G. Bures, Y. C. Martin, and P. Willett, Tbp. Stereochem., 21, 467 (1994). Searching Techniques for Databases of Three-Dimensional Chemical Structures. 

The reaction database compiled on Biochemical Pathways can be accessed on the web and can be investigated with the retrieval system C ROL (Compound Access and Retrieval On Line) [211 that provides a variety of powerful search techniques. The Biochemical Pathways database is split into a database of chemical structures and a database of chemical reactions that can be searched independently but which have been provided with efficient crosslinks between these two databases. 

Koch et al. [111] have discussed the use of graph theoretical techniques in an attempt to find rules to relate beta sheet topology to amino acid sequence and for the comparison of beta sheet structures. They defined a graph representation for every protein in the PDB that contains beta sheets, notations and graphic representations for sheets which described the sequential and topological neighbourhoods of the strands, and constructed tools for substructure searches of this database. 

The new subset-selection methods draw heavily upon the techniques that are used for searching and clustering databases of two-dimensional (2D) and three-dimensional (3D) chemical structures [1-4], These techniques were... 

In the simplest sense, searching chemical information consists of (IXinding structures or reactions that meet the chemist s search criteria and/or (2) finding data that meets the search criteria. Data searching (numbers and text) is a well-established informatics activity, supported by spreadsheets, word processors, and relational database systems. Chemical structures and reactions are a unique form of data. Searching for full or partial matches to structures, models, and reactions requires highly specialized databases and search techniques. 

It is well known that the eyeball technique has a variety of limitations. These are significant in all those cases when there is no way to transform the seenario into a representation where human senses are able to recognize data or features. Another limitation is related to the large number of objects within a search. If one has to check all the molecules stored in a structural database (lO -lO molecular structures) to find those molecules... 

A recent successful application of these methods was the work at Roche on DNA gyrase [146]. The LUDI maps for this site are shown in Fig. 4.6. Pharmacophores derived from these maps were used to search the corporate database using LUDI and Catalyst. Structures were deliberately chosen to be of low molecular weight and were screened at high concentration, so-called needle screening. The subsequent actives were then further developed via structure-based design techniques and medicinal chemistry to give several different series of active compounds. 

In a broad sense, the term computational chemistry includes several fields such as quantum chemistry, statistical molecular mechanics, molecular modeling, approaches based on graph invariants, molecular graphics and visualization, evaluation of experimental data in X-ray crystallography, NMR spectroscopy, and, in general, spectroscopic techniques moreover, in this broad sense, analysis, exploration, and modeling performed by chemometrics on experimental data, searching for structure-response correlations, information retrieval from chemical databases, and expert chemical systems are also included in computational chemistry, as constitutive parts of —> chemoinformatics. 

The pharmacophore models produced are then used as the query for 3D searching techniques, which try to find from a large database of potential lead compounds those that meet the geometrical requirements of the model. Compounds that are found to contain the correct arrangement are called hits and are candidates for screening. These hits differ from the substructure or 2D similarity hits in that the backbone of the structure may be quite different from that of the original lead compound and often represents an important new area of chemistry to be explored. 

Our approach to this chapter is best described as experimental rather than mathematical. There are many excellent formal texts, some of which will be cited. Here, we wish to summarize the fundamental purpose of each technique, to explore its possible applications and limitations, and to illustrate (or provide references to) its use in systematic studies of molecular structure. Most of the examples have been drawn from the Cambridge Structural Database [2], using the methods of search and retrieval detailed in the preceding chapter. We preface the statistical content with two more general chemical sections in the first we discuss the selection of geometric parameters that are most appropriate for certain types of analysis, whilst in the second we discuss the possible sources of variation in crystallographic structural data. 

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