Wolf-Dietrich Ihlenfeldt

Enhanced CACTVS Browser of the Open NCI Database

A Web-based, graphical user interface has been developed to conduct rapid searches by numerous criteria in the more than 250,000 structures of the Open NCI Database. It is based on the chemistry information toolkit CACTVS. Nearly all structures and anticancer and anti-HIV screening data provided by NCIs Developmental Therapeutics Program have been included. This data set has been augmented by a large amount of additional, mostly computed, data, such as calculated log P values, predicted biological activities, systematically determined names, and others. Complex boolean searches are possible. Flexible substructure searches have been implemented. The user can conduct 3D pharmacophore queries in up to 25 conformations precalculated for each compound. Numerous output formats as well as 2D and 3D visualization options are provided. It is possible to export search results in various forms and with choices for data contents in the exported files, for structure sets ranging in size from a single compound to the entire database. Only a Web browser is needed to use this service, with a few plug-ins being useful but optional.

The Impact of Tautomer Forms on Pharmacophore-Based Virtual Screening†

In the field of in silico screening, many applications do not automatically consider possible tautomeric states of molecules. However, the detection of new compound candidates might rely on correct structural description, which is important for the perfect fit toward the biologically relevant interactions. In this paper, we present a new exhaustive tautomer enumeration approach implemented by means of the CACTVS software package. The approach contains a set of 21 predefined SMIRKS-based transforms and a powerful transformation engine that is capable of generating most tautomers described comprehensively in the literature or found in databases in the field of medicinal chemistry. User-defined tautomer rules applied to specific structural databases or scientific issues can be implemented easily and used instead of the predefined rules. In addition, we describe the impact of tautomer-enriched databases on pharmacophore screening approaches for human matrix metalloproteinase 8 as an example of a protein-based pharmacophore screening scenario and for human cyclin-dependent kinases as an example of a ligand-based pharmacophore screening approach. In both test cases, as a preprocessing step, we have used our new tautomer enumerator tool for the tautomer enrichment of the screening data sets and have used it as a postprocessing step to remove tautomeric duplicates from the results. We could demonstrate that the tautomer-enriched screening data sets show significant advantages compared to their non-enhanced counterparts. The discrimination between hits and nonhits was significantly better in the case of tautomer-enriched databases. Moreover, it has been proved that tautomer-enhanced databases will lead to a higher number of potential hits.

Tautomerism in large databases

We have used the Chemical Structure DataBase (CSDB) of the NCI CADD Group, an aggregated collection of over 150 small-molecule databases totaling 103.5 million structure records, to conduct tautomerism analyses on one of the largest currently existing sets of real (i.e. not computer-generated) compounds. This analysis was carried out using calculable chemical structure identifiers developed by the NCI CADD Group, based on hash codes available in the chemoinformatics toolkit CACTVS and a newly developed scoring scheme to define a canonical tautomer for any encountered structure. CACTVS’s tautomerism definition, a set of 21 transform rules expressed in SMIRKS line notation, was used, which takes a comprehensive stance as to the possible types of tautomeric interconversion included. Tautomerism was found to be possible for more than 2/3 of the unique structures in the CSDB. A total of 680 million tautomers were calculated from, and including, the original structure records. Tautomerism overlap within the same individual database (i.e. at least one other entry was present that was really only a different tautomeric representation of the same compound) was found at an average rate of 0.3% of the original structure records, with values as high as nearly 2% for some of the databases in CSDB. Projected onto the set of unique structures (by FICuS identifier), this still occurred in about 1.5% of the cases. Tautomeric overlap across all constituent databases in CSDB was found for nearly 10% of the records in the collection.

InfVis - Platform-Independent Visual Data Mining of Multidimensional Chemical Data Sets

The tremendous increase of chemical data sets, both in size and number, and the simultaneous desire to speed up the drug discovery process has resulted in an increasing need for a new generation of computational tools that assist in the extraction of information from data and allow for rapid and in-depth data mining. During recent years, visual data mining has become an important tool within the life sciences and drug discovery area with the potential to help avoiding data analysis from turning into a bottleneck. In this paper, we present InfVis, a platform-independent visual data mining tool for chemists, who usually only have little experience with classical data mining tools, for the visualization, exploration, and analysis of multivariate data sets. InfVis represents multidimensional data sets by using intuitive 3D glyph information visualization techniques. Interactive and dynamic tools such as dynamic query devices allow real-time, interactive data set manipulations and support the user in the identification of relationships and patterns. InfVis has been implemented in Java and Java3D and can be run on a broad range of platforms and operating systems. It can also be embedded as an applet in Web-based interfaces. We will present in this paper examples detailing the analysis of a reaction database that demonstrate how InfVis assists chemists in identifying and extracting hidden information.

Digital Watermarking of Chemical Structure Sets

The information about 3D atomic coordinates of chemical structures is valuable knowledge in many respect. For large sets of different structures, the computation or measurement of these coordinates is an expensive process. Therefore, the originator of such a data set is interested in enforcing his intellectual property right. In this paper, a method for copyright protection of chemical structure sets based on digital watermarking is proposed. A complete watermarking system including synchronization of the watermark detector and verification of the decoded watermark message is presented. The basic embedding scheme, denoted SCS (Scalar Costa Scheme) watermarking, is based on considering watermarking as a communications problem with side information at the encoder.

Visualizing chemical data in the internet—data-driven and interactive graphics

Abstract Chemistry faces interesting problems with regard to internet-based information visualization, especially in the context of digital library documents with multimedia components. We have developed a number of methods and applications ranging from the automatic generation of 2D structure sketches to 3D volume interactive visualization of molecular data with iso-surfaces and other 3D visualization techniques. This article gives an overview about these techniques and their potential for digital publishing and information indexing.

An efficient approach toward a flexible and general knowledge definition and program control language system for a synthesis-planning program

The concept and implementation of an embedded program control and knowledge encapsulation language pair is presented. It is efficient both in terms of execution speed and implementation effort. The WODCA synthesis-planning system uses this language set for a wide variety of tasks including complex rulebased operations such as strategic bond detection and merit evaluation of possible starting materials. Important features of the language pair include interactive run-time function development and modification, interactive debugging, and cross-compilation techniques for a maximum of code maintainability and execution efficiency.

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