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CBI/JSBi Sponsored Session - Abstracts

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http://cbi-society.org/cbi/taikai/taikai11/index_e.html

Edgar Wingender:
"Efficient large-scale screening of chemical structures for potential biological activities"

"The geneXplain platform: from functional genome analysis to biological process simulation"

"One out of 24 million: How to computationally identify a new candidate drug against breast cancer"

geneXplain GmbH

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  • 1. Efficient large-scale screening of chemical structures for potential biological activitiesMaking use of a very large data basis that has been gathered over about 40 years, the software PASScan efficiently predict biological activities of chemical substances. The acronym PASS stands forPrediction of Activity Spectra for Substances. This allows the evaluation of the biological activityprofiles for compounds even prior to their chemical synthesis and biological testing. Moreover, theprogram also estimates the influence of single atoms on the overall activity of the molecule. Thus,PASS can be used to systematically optimize a chemical structure with regard to desired effects, andto minimize undesired side-effects. Along with another supporting program, PharmaExpert,systematic data mining can be done to select those compounds out of a broad range of substancesthat are the most promising ones for a certain purpose. Finally, a user can also load own data aboutstructure-activity relations as new training sets to create a proprietary structure-activity relationshipbase for the program.Multilevel Neighborhoods of Atoms (MNA) descriptors have been selected to describe the 2Dstructural formulae of organic compounds. The molecular structure is represented in PASS by the setof MNA descriptors of the 1st and 2nd levels. The prediction algorithm is based on Bayesian estimatesof probabilities for a compound to belong to the classes of active or inactive compounds,respectively.The current version of PASS (11.4.12) predicts 4,444 kinds of biological activity with an averageprediction accuracy of 95%.The geneXplain platform: from functional genome analysis to biological process simulationThe geneXplain platform is an online toolbox and workflow management system for a broad range ofbioinformatic and systems biological applications. The individual modules are unified under astandardized interface with a consistent look-and-feel and can be flexibly put together tocomprehensive workflows. The functionalities provided by the platform range from storage andstatistical processing of (e.g.) genomics or transcriptomics raw data through gene set enrichmentanalysis, cluster analysis and identification of master regulators for a biological process to thesimulation of the dynamic behavior of a network.A number of complex standard applications have been composed to pre-defined workflows. They canbe customized through a workflow management that is handled through a simple drag-and-dropsystem also supporting the design of own workflows. Also, own scripts can be included into thesystem and used in combination with pre-existing analyses.It should be noticed that the platform provides a number of state-of-the-art modules; some of themcan be obtained free of charge, while others require licensing for small fee in order to guaranteeactive maintenance and dynamic adaptation to the rapidly developing know-how in this field. Weexplicitly encourage the community to contribute their own modules, which will be made availableand supported by the geneXplain platform.
  • 2. One out of 24 million: How to computationally identify a new candidate drug against breast cancerApoptosis of breast cancer cells can be induced by the known drug RITA. However, at doses where itefficiently induces p53-mediated apoptosis, it does not fully support p53-dependent inhibition ofsurvival genes, allowing some tumor cells to escape from apoptosis. In an attempt to find a way tosuppress survival genes as well, transcriptomics data of breast cancer cells were investigated usingthe geneXplain platform technology. Comprehensive promoter and network analysis revealed anumber of potential master regulator genes. In a next step, the PASS approach was applied toidentify multitargeted compounds, i.e. substances that could inhibit with several master regulatormolecules at the same time. This way, and going subsequently through several filtering steps, 24million chemical substances from the ChemNavigator library were virtually screened, leaving 64compounds as potentially active ones. Of them, 26 turned out to be feasible for experimental testing,out of which 2 substances exhibited highly specific effects.Altogether, we conclude that our general strategy of integrated bioinformatic, systems biological andcheminformatics analysis is highly suitable to identify promising lead structures for drugdevelopment.GeneXplain GmbH, Wolfenbuettel, GermanyGeneXplain is still a relatively young company, with the mission to provide a comprehensive platformfor bioinformatic, cheminformatic and systems biological tools. The raison dêtre of this platform is toassist translational research in the life sciences, mainly in the context of personalized medicine andpharmacogenomics. We also make our expertise available to academic and commercial partners incollaborative research projects.Our strong commitment to science and research prompts us to seek for a new way of collaboration.We feel that only by combining academic creativity with private commercial efforts, it will bepossible to generate a research platform that is both at the most recent state of the art as well asreliable supported.At present, geneXplain’s product portfolio comprises the cheminformatics tools PASS, PharmaExpertand GUSAR, as well as the bioinformatics / systems biological geneXplain platform. In addition, wedistribute the software packages IMC (In-silico Molecular Cloning) and Genome Traveler outsideJapan for our partner in silico biology, inc in Yokohama.

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