Three-dimensional structure searching types

The science community has clearly established the essential role which protein and DNA sequences play in the understanding of biological systems. The sequences themselves are informative Indeed, many software tools are available which allow to make sense of the primary sequence information. Take those that analyse protein sequences for domains and active sites, perform similarity and homology searches, or predict the three-dimensional structure or physico-chemical parameters. However, raw sequences contain insufficient information, per se. One cannot infer any description or understanding of the level of expression of the active proteins, the content of post-translational modifications (PTMs), the tertiary structure and, what is perhaps the most relevant information, a protein s function. Like the sequences themselves, all these added value data need to be captured in various databases. These databases have to be queried by different types of users in proteomics and should therefore be easily searchable by software tools and be inter-linked in order to document the correspondences between the type of information provided by the different databases. 

While atomic coordinates form the fundamental structure of a molecule, many methods prefer to represent a three-dimensional structure as a surface or a shape. Of course, these are ultimately computed from the atomic coordinates and perhaps atomic partial charges. It may be possible to represent these molecular surfaces or shapes as an array of three-dimensional coordinates. These could be stored as a column in the database analogous to the array of atomic coordinates. It might be necessary to create another data type, perhaps a composite data type, to store molecular surfaces or shapes. Once these representations are stored, they can be used in new SQL functions to assist in searching based on molecular surface or shape. 

Another critical question relates to the development of a pharmacology for neuronal Ca " channels. While L-type Ca " channels have a rich pharmacology that has provided novel therapeutic approaches to treat cardiovascular diseases, nonpeptide molecules, which block or inactivate the N, P, Q, T, or R channels, are lacking. Thus, a major goal for research in this field is the search for selective blockers or modulators of specific Ca " channel subtypes that could eventually be used as therapeutic tools in disease. The recent introduction of mibefradil as a T-type Ca " channel blocker opened new possibilities to study the functions of these channels. The knowledge of the three-dimensional structure in solution of the different toxins is very important for studying the specificity of their interactions with Ca " channel subtypes, and to define active sites that can... 

The number of spanning trees, pairs of nucleotide contacts and homogeneous transformation matrices associated with a contact graph determine the conformational search space size of a RNA. The number of homogeneous transformation matrices associated with a molecular contact type is given by the number of occurrences observed in all available RNA three-dimensional structures in the Protein DataBank (PDB) (7), Nucleic acids DataBase (NDB) (5) and other personally communicated structures. 

A module of the CHEM-X modelling system (see modelling section). Storage and retrieval of two- and three-dimensional structures with substructure-search capability. Available databases include Chapman Hall Dictionary of Drugs (15,000 compounds). Chapman Hall Dictionary of Fine Chemicals (120,000 small organics). Chapman Hall Dictionary of Natural Products (54,000), Derwent Standard Drug File (31,000 biologically active compounds), ChemReact (370,000 reaction types) and others. 

Recently, Wipke and Rogers described superstructure searching, which retrieves those molecules that are contained within the query structure, rather than the inverse. The same bit maps are used the difference is that for a substructure search the bit screen of the hit must contain all of the query bits, whereas for a superstructure search the query must contain all of the bits present in the hit. This type of search has applications in computer-aided design of synthetic pathways and in building three-dimensional structures from three-dimensional fragments. ... 

The type of features that are typically used in our size and shape searching are generic 3D triangle and 3D tetrangle features which are derived from 3D structures generated by the CONCORD program (see Three-dimensional Structure Generation Automation). 

In this chapter, we will discuss the present status of CHIRBASE and describe the various ways in which two (2D) or three-dimensional (3D) chemical structure queries can be built and submitted to the searching system. In particular, the ability of this information system to locate and display neighboring compounds in which specified molecular fragments or partial structures are attached is one of the most important features because this is precisely the type of query that chemists are inclined to express and interpret the answers. Another aspect of the project has been concerned with the interdisciplinary use of CHIRBASE. We have attempted to produce a series of interactive tools that are designed to help the specialists or novices from different fields who have no particular expertise in chiral chromatography or in searching a chemical database. 

Quantitative Structure-Activity Relationship models are used increasingly in chemical data mining and combinatorial library design [5, 6]. For example, three-dimensional (3-D) stereoelectronic pharmacophore based on QSAR modeling was used recently to search the National Cancer Institute Repository of Small Molecules [7] to find new leads for inhibiting HIV type 1 reverse transcriptase at the nonnucleoside binding site [8]. A descriptor pharmacophore concept was introduced by us recently [9] on the basis of variable selection QSAR the descriptor pharmacophore is defined as a subset of... 

Since the end of the seventies, interest in cyclotriveratrylene has moved towards the use of its cone shaped structure for applications in various fields, including investigations of the electronic transitions of the benzene chromophore via UV and CD spectroscopy, studies in the area of host-guest chemistry, synthesis of new types of liquid crystals, and searches for new three-dimensional organic charge-transfer materials. These works have been made possible because efficient synthetic... 

Some examples from our recent study of opiate analgesic structures (8,24) serve to illustrate further the types of information which a combined approach can provide. The approach used in this study was 1) accumulate accurate crystal structure results on representative compounds by literature search and performing crystal structure determinations, then 2) develop and verify molecular mechanics potential parameters for use with analgesics, and 3) perform strain energy calculations to find active conformations by comparing different chemical structural types which act at a common receptor. The object of the study was to 1) better define the three-dimensional requirements of opiate analgesics, and 2) better understand the opiate receptor itself by indirectly investigating it. 

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