| 1. |
- Leist, Marcel, et al.
(författare)
-
Adverse outcome pathways : opportunities, limitations and open questions
- 2017
-
Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:11, s. 3477-3505
-
Tidskriftsartikel (refereegranskat)abstract
- Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event erelationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.
|
|
| 2. |
- Spjuth, Ola, 1977-, et al.
(författare)
-
XMetDB : an open access database for xenobiotic metabolism
- 2016
-
Ingår i: Journal of Cheminformatics. - : Springer Science and Business Media LLC. - 1758-2946. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Xenobiotic metabolism is an active research topic but the limited amount of openly available high-quality biotransformation data constrains predictive modeling. Current database often default to commonly available information: which enzyme metabolizes a compound, but neither experimental conditions nor the atoms that undergo metabolization are captured. We present XMetDB, an open access database for drugs and other xenobiotics and their respective metabolites. The database contains chemical structures of xenobiotic biotransformations with substrate atoms annotated as reaction centra, the resulting product formed, and the catalyzing enzyme, type of experiment, and literature references. Associated with the database is a web interface for the submission and retrieval of experimental metabolite data for drugs and other xenobiotics in various formats, and a web API for programmatic access is also available. The database is open for data deposition, and a curation scheme is in place for quality control. An extensive guide on how to enter experimental data into is available from the XMetDB wiki. XMetDB formalizes how biotransformation data should be reported, and the openly available systematically labeled data is a big step forward towards better models for predictive metabolism.
|
|
| 3. |
- Wilkinson, Mark D., et al.
(författare)
-
Comment : The FAIR Guiding Principles for scientific data management and stewardship
- 2016
-
Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders-representing academia, industry, funding agencies, and scholarly publishers-have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community.
|
|
| 4. |
- Willighagen, Egon L., et al.
(författare)
-
The Chemistry Development Kit (CDK) v2.0 : atom typing, depiction, molecular formulas, and substructure searching
- 2017
-
Ingår i: Journal of Cheminformatics. - : Springer Science and Business Media LLC. - 1758-2946. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The Chemistry Development Kit (CDK) is a widely used open source cheminformatics toolkit, providing data structures to represent chemical concepts along with methods to manipulate such structures and perform computations on them. The library implements a wide variety of cheminformatics algorithms ranging from chemical structure canonicalization to molecular descriptor calculations and pharmacophore perception. It is used in drug discovery, metabolomics, and toxicology. Over the last 10 years, the code base has grown significantly, however, resulting in many complex interdependencies among components and poor performance of many algorithms.Results: We report improvements to the CDK v2.0 since the v1.2 release series, specifically addressing the increased functional complexity and poor performance. We first summarize the addition of new functionality, such atom typing and molecular formula handling, and improvement to existing functionality that has led to significantly better performance for substructure searching, molecular fingerprints, and rendering of molecules. Second, we outline how the CDK has evolved with respect to quality control and the approaches we have adopted to ensure stability, including a code review mechanism.Conclusions: This paper highlights our continued efforts to provide a community driven, open source cheminformatics library, and shows that such collaborative projects can thrive over extended periods of time, resulting in a high-quality and performant library. By taking advantage of community support and contributions, we show that an open source cheminformatics project can act as a peer reviewed publishing platform for scientific computing software.
|
|
