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      ToxAlerts: A Web Server of Structural Alerts for Toxic Chemicals and Compounds with Potential Adverse Reactions

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          Abstract

          The article presents a Web-based platform for collecting and storing toxicological structural alerts from literature and for virtual screening of chemical libraries to flag potentially toxic chemicals and compounds that can cause adverse side effects. An alert is uniquely identified by a SMARTS template, a toxicological endpoint, and a publication where the alert was described. Additionally, the system allows storing complementary information such as name, comments, and mechanism of action, as well as other data. Most importantly, the platform can be easily used for fast virtual screening of large chemical datasets, focused libraries, or newly designed compounds against the toxicological alerts, providing a detailed profile of the chemicals grouped by structural alerts and endpoints. Such a facility can be used for decision making regarding whether a compound should be tested experimentally, validated with available QSAR models, or eliminated from consideration altogether. The alert-based screening can also be helpful for an easier interpretation of more complex QSAR models. The system is publicly accessible and tightly integrated with the Online Chemical Modeling Environment (OCHEM, http://ochem.eu). The system is open and expandable: any registered OCHEM user can introduce new alerts, browse, edit alerts introduced by other users, and virtually screen his/her data sets against all or selected alerts. The user sets being passed through the structural alerts can be used at OCHEM for other typical tasks: exporting in a wide variety of formats, development of QSAR models, additional filtering by other criteria, etc. The database already contains almost 600 structural alerts for such endpoints as mutagenicity, carcinogenicity, skin sensitization, compounds that undergo metabolic activation, and compounds that form reactive metabolites and, thus, can cause adverse reactions. The ToxAlerts platform is accessible on the Web at http://ochem.eu/alerts, and it is constantly growing.

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          Most cited references18

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          Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information

          The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu.
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            Derivation and validation of toxicophores for mutagenicity prediction.

            Mutagenicity is one of the numerous adverse properties of a compound that hampers its potential to become a marketable drug. Toxic properties can often be related to chemical structure, more specifically, to particular substructures, which are generally identified as toxicophores. A number of toxicophores have already been identified in the literature. This study aims at increasing the current degree of reliability and accuracy of mutagenicity predictions by identifying novel toxicophores from the application of new criteria for toxicophore rule derivation and validation to a considerably sized mutagenicity dataset. For this purpose, a dataset of 4337 molecular structures with corresponding Ames test data (2401 mutagens and 1936 nonmutagens) was constructed. An initial substructure-search of this dataset showed that most mutagens were detected by applying only eight general toxicophores. From these eight, more specific toxicophores were derived and approved by employing chemical and mechanistic knowledge in combination with statistical criteria. A final set of 29 toxicophores containing new substructures was assembled that could classify the mutagenicity of the investigated dataset with a total classification error of 18%. Furthermore, mutagenicity predictions of an independent validation set of 535 compounds were performed with an error percentage of 15%. Since these error percentages approach the average interlaboratory reproducibility error of Ames tests, which is 15%, it was concluded that these toxicophores can be applied to risk assessment processes and can guide the design of chemical libraries for hit and lead optimization.
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              Can we estimate the accuracy of ADME-Tox predictions?

              There have recently been developments in the methods used to access the accuracy of the prediction and applicability domain of absorption, distribution, metabolism, excretion and toxicity models, and also in the methods used to predict the physicochemical properties of compounds in the early stages of drug development. The methods are classified into two main groups: those based on the analysis of similarity of molecules, and those based on the analysis of calculated properties. An analysis of octanol-water distribution coefficients is used to exemplify the consistency of estimated and calculated accuracy of the ALOGPS program (http://www.vcclab.org) to predict in-house and publicly available datasets.
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                Author and article information

                Journal
                J Chem Inf Model
                J Chem Inf Model
                ci
                jcisd8
                Journal of Chemical Information and Modeling
                American Chemical Society
                1549-9596
                1549-960X
                10 August 2012
                27 August 2012
                : 52
                : 8
                : 2310-2316
                Affiliations
                []eADMET GmbH , Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany
                []Institute of Organic Synthesis of the Ural Department of the Russian Academy of Sciences , 620069 Ekaterinburg, Russia
                [§ ]Pharmaceutical Chemistry, Chelyabinsk State Medical Academy , Chelyabinsk, Russian Federation 454048
                []Medicinal Chemistry Platform, Ontario Institute for Cancer Research , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario, Canada M5G 0A3
                []Institute of Structural Biology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health , Ingolstädter Landstraße 1, b. 60w D-85764 Neuherberg, Germany
                Author notes
                [* ]Tel.: +49-89-3187 3575. Fax: +49-89-3187 3585. E-mail: itetko@ 123456vcclab.org .
                Article
                10.1021/ci300245q
                3640409
                22876798
                9a9c5b67-7499-4dda-bc62-dee2865a7c59
                Copyright © 2012 American Chemical Society
                History
                : 24 May 2012
                Categories
                Article
                Custom metadata
                ci300245q
                ci-2012-00245q

                Computational chemistry & Modeling
                Computational chemistry & Modeling

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