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1、QSAR Application Toolbox: First Steps - Data Gap Filling (Read-Across by Analogue Approach),Background,This is a step-by-step presentation designed to take the first time user of the Toolbox through the workflow of the least complex of the data filling exercises.This presentation reflects the “Getti
2、ng Started” document available at www.oecd.org/env/existingchemicals/qsar,Objectives,This presentation demonstrates a number of functionalities of the Toolbox : Identify analogues for a target chemical, Retrieve experimental results available for those analogues, and Fill data gaps by read-across.,S
3、pecific Aims,To introduce the first time user to the work flow of the Toolbox. To familiarize the first time user with the six modules of the Toolbox. To familiarize the first time user with the basic functionalities within each module. To explain to the first time user the rationale behind each ste
4、p of the exercise.,The Exercise,In this exercise we will predict the skin sensitization potential for an untested compound, (4-nitrobenzoyl chloride) CAS # 122-04-3, which will be the “target” chemical. This prediction will be accomplished by collecting a small set of test data for chemicals conside
5、red to be in the same category as the target molecule. The category will be defined by the mechanism of protein binding common to all the chemicals in the category. The prediction itself will be made by “read-across”.,Read-across & the Analogue Approach,Read-across can be used to estimate missing da
6、ta from a single or limited number of chemicals using an analogue approach. In the analogue approach, endpoint information for a single or small number of tested chemicals is used to predict the same endpoint for an untested chemical that is considered to be “similar.” Analogous sets of chemicals ar
7、e often selected based on the hypothesis that the toxicological effects of each member of the set will show a common behavior.,Side-Bar On Sensitization,Allergic contact dermatitis that results from skin sensitization is a significant health concern. Skin sensitization is a toxicological endpoint th
8、at is complex and conceptually difficult. However, there is growing agreement that all organic chemicals must react covalently with skin protein in order to behave as skin sensitizers. Therefore, mechanism by which organic chemicals bind with proteins are relevant to grouping chemicals that may be s
9、kin sensitizing agents.,Tracks,After opening the Toolbox, the user has to choose between three use tracks (or workflows): (Q)SAR Track Category Track Flexible Track For a first time users of the Toolbox, it is recommended to select the Category Track. As the user becomes more familiar with the funct
10、ionalities of the Toolbox, it is recommended to use the Flexible Track.,Workflow,Each track follows the same general six-step workflow: Chemical Input Profiling Endpoints Category Definition Filling Data Gaps Reporting,Tracks and Workflow,Chemical Input,Click on the “Category Track”. This takes you
11、to the first module, which is “Chemical input”. This module provides the user with several means of entering the chemical of interest or the target chemical. Since all subsequent functions are based on chemical structure, the goal here is to make sure the molecular structure assigned is the correct
12、one.,Chemical Input Screen,Ways of Entering a Chemical,There are several ways to enter a target chemical. Most often used are: Chemical Abstract Services (CAS) number (#), SMILES (simplified molecular information line entry system) notation, and Drawing the structure using the structural editor incl
13、uded in the Toolbox. Click on CAS#.,Enter CAS # 122043; Click on Search,The Search for the Structure,The Toolbox now searches the databases to find out if the CAS# you entered is linked to a molecular structure stored in the Toolbox. If the structure is identified, it is displayed as a 2D image.,Cli
14、ck on OK to Accept Target,Target Chemical,You have now selected your target chemical and have a structure for it. This is important as from here on the workflow will be based on the structure coded in SMILES. Click on the box next to “Substance Information”; this displays the chemical identification
15、 information. The workflow on the first module is now complete; Click “Next” to move to the module “Profiling”,Chemical Identification Information,Profiling,“Profiling” refers to the electronic process of retrieving relevant information on the target compound, other than environmental fate, ecotoxic
16、ity, and toxicity data, which are stored in the Toolbox. Available information includes likely mechanism(s) of action.,Profiling Target Chemical,Select the “Profiling methods” you wish to use. When first using the Toolbox, all the profiling methods are pre-selected (red checked boxes). You can therefore deselect (red check disappears) those profilers you DO NOT wish to use by clicking on the red checked box before the name of the profiler. For this example, deselect all the profilers except for the “mechanistic” methods. Click on “Apply”.,
