Toxtree user manual
Contents
1. Class I substances are simple chemical structures with efficient modes of metabolism suggesting a low order of oral toxicity Class IM substances ate those that permit no strong initial presumption of safety or may even suggest significant toxicity or have reactive functional groups and finally Class II are intermediate This plug in was developed by Ideaconsult Ltd Sofia Bulgaria on behalf of JRC Mote details at http toxtree sourceforge net cramer html Exercise 2 Biodegradability Typical use of Toxtree could follow the following scenario 1 change the decision tree used in the estimation through the Toxtree MethodP Select decision tree menu Select START Biodegradability enter a the following chemical name in the INPUT AREA field 2 2 iminodiethanol press Estimate on the right upper part of the application window read the toxic hazard classification of the structure by application of START Biodegradability Class1 easily biodegradable chemical in this case read the classification explanation which rules have been applied enter a the following chemical name in the INPUT AREA field 2S 3S 5R 3 methyl 7 oxo 3 1H 1 2 3 triazol 1 ylmethyl 4 thia 1 azabicyclo 3 2 0 heptane 2 carboxylic acid 4 4 dioxide press Estimate on the right upper part of the application window TOXTREE USER MANUAL 8 read the toxic hazard classification of the structure by application of START Biodegradability2. Toxtree Course QSAR2014 IDEACONSULT QSAR2014 Toxtree course Ideaconsult Ltd 4 Angel Kanchev St 1000 Sofia Bulgaria Phone 359 886802011 Email jeliazkova nina gmail com Version of 15 June 2014 Table of Contents Download Prerequisites Toxtree distributions Windows Toxtree setup Toxtree setup for other OS Launching Toxtree Main screen layout Exercise 1 Cramer rules Exercise 2 Biodegradability Exercise 3 Batch processing oN U Q N Kee he eR KN Further readings Opening saving a file Decision tree visualisation Exercise 4 Toxtree online NN A N N N TOXTREE USER MANUAL Download e Open http toxtree sourceforge net in a web browser Download Toxtree 2 6 6 http toxtree sourceforge net download html Toxtree_2 6 6 Select Windows installer option for Windows or ZIP archive for Linux or Mac Prerequisites Toxtree requires Java 2 Runtime Environment Standard Edition 1 7 or newer on the target system and it is platform independent It runs under any host operating system which supports Java 2 Runtime Environment Standard Edition Toxtree distnbutions Toxtree is distributed in two different ways ZIP archive containing the complete documented Java source code binaries example lists of compounds installation manual and user manual Windows NT 2000 XP or 2003 standalone offline automa
3. Class2 persistent chemical 9 read the classification explanation which rules have been applied 10 enter a the following EINECS number in the INPUT AREA field 205 288 3 11 press Estimate on the right upper part of the application window 12 read the toxic hazard classification of the structure by application of START Biodegradability Class2 persistent chemical 13 read the classification explanation which rules have been applied The answer Q18 Tertiary amine is positive click on the blue link Q18 Tertiary amine in order to highlight the tertiary amine substructure 14 consult the decision tree accessible through the Toxtree Method View decision tree menu Background START Structural Alerts for Reactivity in Toxtree biodegradation and persistence plug in A compilation of structural alerts for environmental persistence and biodegradability These structural alerts are molecular functional groups or substructures that are known to be linked to the environmental persistence or biodegradability of chemicals The rulebase utilizes the structural alerts in logical decision trees If one or more the structural alerts embedded in the molecular structure of the chemical are recognized the system flags the potential persistence or biodegradability of the chemical Installation and user manual is available online This plug in was developed by Molecular Networks GmbH Erlangen Germany http toxtree so
4. Noto all Available structure attributes ALERTSCounter Jo 0000 Comment Created From SMILES FORMULA C6H 7N SMILES ciccccciN Title ciccccc1N Figure 3 Options for QSAR6 and QSAR8 calculations User input For a better assessment of a b unsaturated aldehyde QSAR calculation could be applied Would you like to proceed Warning the assessment could be time consuming Proceed with QSAR13 Yes OQONo Yestoall Noto all Available structure attributes 4LERTSCounter 1 0000 Comment Created From SMILES FORMULA C7H120 SMILES CCCCC CC 0 Figure 4 Options for QSAR13 calculations The available options have the following semantics 10 TOXTREE USER MANUAL e Yes The QSAR will be calculated for the current chemical and the question dialog will appear for each subsequent chemical e No The QSAR will not be calculated for the current chemical and the question dialog will appear for each subsequent chemical e Yes to all The QSAR will be calculated for the current chemical and for all subsequently processed chemicals for which it is applicable The question dialog will not appear anymore unless the option is changed via the Method Decision Tree Options menu e Noto all The QSAR will be not calculated for the current chemical and for all subsequently processed chemicals for which it is applicable The question dialog will not appear anymore unless th
5. 0 Daltons Yes 1 1 Not contain Ifl Yes 1 2 Not contain ionic groups Yes Q1 3 Contain only C amp H No Q1 4 Contain only C H and halogen No 1 5 Contain C H amp O C O Yes Q1 5 1 Be linear ethers or monocyclic mono ethers but not epoxides or peroxides No Q1 5 2 Be aliphatic alcohols but not allylic propargylic alcohols No Q1 5 3 Be alcohols with aromatic moieties but NOT phenols or benzylic alcohols No Q1 5 4 Be ketones but not alpha beta unsaturated ketones e g 1 butenone or acetophenone No Q2 1 Be non or weakly acidic phenols No Q2 2 Be anilines with one nitro substituent and or one to three chlorine substituents and or alkyl substituents No Q2 3 Be mononitroaromatics with one or two chlorine substituents and or alkyl substituents No Q2 4 Be primary alkyl amines containing only C H N No Click on the 7 button next to Toxicity prediction modules in order to launch the toxicity estimation 14
6. 2 Runtime Environment Standard Edition installer for your system Launching Toxtree In Windows platforms Toxtree can be launched either by using the Start menu ot by double clicking on the Toxtree X Y Z jar file the full path name is C Ideaconsult Toxtree vX Y Z Toxtree Toxtree X Y Z jar TOXTREE USER MANUAL In all platforms having Java 2 Runtime Standard Edition 1 7 or newer installed Toxtree can be launched by executing the following command after decompressing the ZIP archive distribution of Toxtree java jar Toxtree X Y Z jar Please note that in the above mentioned command java and Toxtree X Y Z jar should be eventually prefixed with the full path to java and Toxtree on the destination platform Main screen layout The main Toxtree application window comprises a title bar menu bar data areas button bar and status bar The data areas are highlighted in Figure 1 in several different colours and ate labelled in blue The CHEMICAL IDENTIFIER INPUT AREA can be used for entering a SMILES string InChI IUPAC chemical name CAS or EINECS SMILES InChI and IUPAC chemical names ate parsed by Toxtree and structure is generated and displayed in the compound area If CAS or EINECS is entered and the remote queries ate enabled Toxtree will attempt to query a remote OpenTox web setvice in order to retrieve the chemical structure This functionality is disabled by default It can be enab
7. Decision tree visualisation 13 TOXTREE USER MANUAL Exercise 4 Toxtree online Open the following link in a web browser http toxtree sourceforge net redict Enter chemical identifier in the text box e g 50 00 0 and press Query Web edition toxtree sf net J l rde s tweet Fi share RR Toxtree Toxic Hazard Estimation by decision tree approach EA 50 00 0 Available structure attributes CasRN 50 00 0 50 EC number 200 001 8 IUPAC name formaldehy Names formaldehy SMILES C OlfHIC L Std InChI InChl 1S C Std InChl key WSFSSNU REACH regis 30 11 2011 Cramer rules Cramer rules Low Class Extended Cramer rules Cramer rules Low Class Verhaar scheme for predicting toxic Verhaar sche Class 3 ur Verhaar scheme modified for pred Verhaar sche Class 3 ur Protein binding Alert for SNA NO Alert for Schif YES Alert for Mich NO Alert for Acyl NO Alert for SN2 NO No protein bi NO Bi Structure diagram Oo Toxicity prediction modules Cramer rules O Auto z 1 Normal constituent of the body Yes Class Low Class I Extended Cramer rules O Auto z 1 Normal constituent of the body Yes Class Low Class Verhaar scheme for predicting toxicity mode of action O Auto z 0 1 Consists only of C H N O S halogens exluding I S C N O X Yes 0 2 Have a logKow between 0 and 6 Yes 0 3 Have a molecular mass MW not more than 60
8. XT files together with their classification data class amp path by using the File Save menu Decision tree visualisation The current decision tree is accessible through the Method View decision tree menu It is shown in a child window Rule details are printed after clicking on the respective tree nodes Leaves are coloured according to classes BRM 1 yellow IIT red There are example molecules for each rule outcome Yes or No selectable by radio buttons 29 12 TOXTREE USER MANUAL BA Cramer rules BT o 6 Benzene derivative with certain substit 7 Is the substance a benzene derivative bearing a hydrocarbon chains or 1 hydrox Het li eyelie Terpene Jes HO gterocyclig spene bjone or more alkoxy groups one 11 munde Li 20 A 20 are this places in class III safrole myristicin and r lll 21 ae 27 24 H 3 28 BB Feo lt Decision node Q6 Benzene derivative with certain substituents If NO go to Q7 If YES assign High Class IIT Rule ID Rule title 6 Benzene derivative with certain substituents Rule explanation with answer consisting only of ahydrocarbon chains or l hydroxy or hydroxy ester substituted hydrocarbon chains and bjone or more alkoxy groups one of which must be gt o i There are example molecules for each rule outcome Select which one to display Yes branch No branch Figure 6
9. all the molecules loaded from a file by using the batch processing facility Select File Batch processing Select tox_benchmark_N6512 sdf as file to be processed and enter a new file name to store the results e g test csv supported output files are SDF CSV TXT Press Start button z 3 Batch processing Batch processing options In vitro mutagenicity Ames test alerts by ISS Process file F LochNess Toxtree files tox_benchmark_N6512 sdf Store results in F LochNess Toxtree files test csv Load batch confiquration Save batch configuration Batch configuration 6 15 2014 23 6 toxTree io batch BatchProcessing490880 Batch status Batch running Records processed 94 Figure 2 Batch processing 5 Please note the calculation may take a while The batch process may be cancelled at any time TOXTREE USER MANUAL The QSAR calculations can be time consuming due to the requirement to calculate electronic descriptors The software provides options to skip the QSAR calculation and in this case will assign the category For a better assessment a QSAR calculation could be applied Toxtree will show the dialogs at Figure 3 or Figure 4 if a QSAR is to be calculated User input For a better assessment of aromatic amine QS4R calculation could be applied Would you like to proceed Warning the assessment could be time consuming Proceed with QSAR6 and QS4R8 Yes C No Yestoall
10. cal Compounds Toxic Hazard Method Help aie Toxic Hazard TE lLrwutec gt Low Class I Intermediate Class II High Class MI CLASSIFICATION AREA Figure 1 Toxtree main application window Exercise 1 Cramer rules 1 launch the application 2 enter the following SMILES in the INPUT AREA field O C OCC OC O clicccccl C c2cccec2 3 press Estimate on the right upper part of the application window 4 read the toxic hazard classification of the structure by application of Cramer rules GWE in this case 5 read the classification explanation which Cramer rules have been applied TOXTREE USER MANUAL 6 enter the following SMILES in the INPUT AREA field CSCCCN C S 7 press Estimate on the right upper part of the application window 8 read the toxic hazard classification of the structure by application of Cramer rules intermediate class II in this case 9 read the classification explanation which Cramer rules have been applied 10 enter the following SMILES in the INPUT AREA field clcecc2c cl cccc2 NC N S 11 12 13 14 15 16 17 read the toxic hazatd classification of the structure by application of Cramer rules ME in this case save the processed molecule together with classification data class amp path in a file compatible types are CSV SDF amp TXT Click on the Chemical compounds Edit compound menu option This will launch
11. e option is changed via the Method Decision Tree Options menu 6 Once the batch is completed the results are stored in test csv comma delimited file as shown on Figure 5 Figure 5 Sample CSV file with prediction results Background A decision tree for estimating in vitro mutagenicity Ames test Benigni R Bossa C Tcheremenskata O 2013 In vitro cell transformation assays for an integrated alternative assessment of carcinogenicity a data based analysis Mutagenesis 2013 28 1 107 16 This plug in was developed by Istituto Superiore di Sanita Rome Italy and Ideaconsult Ltd Sofia Bulgaria on behalf of JRC http toxtree sourceforge net ames html Further readings User manuals in the doc folder On Windows C Ideaconsult Toxtree v2 6 6 doc 11 TOXTREE USER MANUAL OpeningSaving a file Toxtree can open CML CSV HIN ICHI INCHI MDL MOL MDL SDF MOL2 PDB SMI TXT and XYZ file types Please note that CSV files can be read written by MS Excel Attention should be paid to cells type should be text otherwise MS Excel could interpret show incorrectly their values Also note that input of CSV and TXT requires a column with SMILES heading in order the structure to be read All other fields are optional will be read as molecule properties and displayed as such You can open a supported type of file by using the File Open menu Molecules can be written to SDF CSV or T
12. led by selecting the Remote lookup enabled checkbox in the Method P Decision tree options Options Remote Query menu as shown in the following screenshot http apps ideaconsult net 8080 amb a Pressing the Go button draws the structure diagram of the corresponding compound in the COMPOUND STRUCTURE DIAGRAM AREA TOXTREE USER MANUAL The lt lt and gt gt buttons on the left hand side of the CHEMICAL IDENTIFIER INPUT AREA are used for navigating the history of entered identifiers This is also accessible also by means of a drop down list The COMPOUNDS PROPERTIES AREA is used to summarise the available information about the current compound The FILE BROWSING AREA provides an easy way to navigate through the list of compounds in the current open file The CLASSIFICATION AREA provides access to the Cramer classification results for the current compound Pressing the Estimate button starts the classification routines for the current compound shown both in the COMPOUNDS PROPERTIES AREA and the COMPOUND STRUCTURE DIAGRAM AREA The classification result is shown in graphical form green highlight for class I yellow and as well as in text form The Verbose explanation checkbox determines the level of detail of the text based classification results TOXTREE USER MANUAL Ei Toxtree Estimation of Toxic Hazard A Decision Tree Approach v2 6 6 o File Edit Chemi
13. nt Standard Edition 1 7 setup would be aborted and Toxtree would not be installed If the installer detects Java 2 Runtime Environment Standard Edition 1 7 or newer already installed on the target system it will proceed directly with the Toxtree setup In this case ADMINISTRATIVE PRIVILEGES ARE RECOMMENDED BUT NOT NECESSARILY REQUIRED When the installer is launched by a user with administrative privileges it will create Toxtree start menu shortcuts for all the users registered in the target system Otherwise start menu shortcuts will be created only for the unprivileged user who launched the installation After a successful installation Toxtree could be launched from the Start Menu Start All Programs Ideaconsult Toxtree vX Y Z Toxtree vX Y Z Toxtree setup for other OS Toxtree runs under any host operating system which supports Java 2 Runtime Environment Standard Edition e g Linux FreeBSD Solaris Mac OS etc If youre running such operating system you should download and use the ZIP archive distribution of Toxtree Please note that before attempting to run Toxtree you should check that Java 2 Runtime Environment Standard Edition 1 7 or newer is installed on your system If Java 2 Runtime Environment Standard Edition is missing or an older version is present please obtain from http www oracle com technetwork java javase downloads jdk7 downloads 1880260 html and run the appropriate Java
14. ted installer with integrated Java 2 Runtime Environment Standard Edition 1 7 setup The ZIP archive is suitable for use on any operating system with Java 2 Runtime Environment Standard Edition 1 7 already installed It might be useful also for studying the application source code The Windows installer includes all the contents of the ZIP archive as well as the ability to check for the presence of Java 2 Runtime Environment Standard Edition 1 7 on the target system If the installer does not detect Java 2 Runtime Environment Standard Edition 1 7 already installed on the target system it would attempt to install it prior to Toxtree setup Windows Toxtree setup The Toxtree application is distributed with a fully automated offline installer Toxtree vX Y Z setup exe compatible with recent versions of the Microsoft Windows NT 2000 XP 2003 7 2008 operating system In order to install Toxtree just run the TOXTREE USER MANUAL installer and follow its instructions The installer contains all the required packages including the Java 2 Runtime Environment Standard Edition 1 7 setup If the installer does not detect Java 2 Runtime Environment Standard Edition 1 7 or newer on the target system it will attempt to install it before proceeding with the Toxtree setup In this case the user running the installer SHOULD HAVE ADMINISTRATIVE PRIVILEGES on the target system otherwise the Java 2 Runtime Environme
15. the JChemPaint structure diagram editor and allows editing the current structure Edit the structure Click OK when ready This will update the structure displayed on the main screen Click again on the Estimate button This will apply the decision tree to the new structure read the toxic hazard classification of the structure by application of Cramer rules read the classification explanation which structure alerts have been verified Click on blue links to highlight the structure alerts found save the processed molecule together with classification data class amp path in a file compatible types are CSV SDF amp TXT Please note that CSV files can be read written by MS Excel Cramer rules background The threshold of toxicological concern ITC is an open research topic with significant practical implications Two principal approaches exist in the thresholds developed to 1 More information about JChemPaint can be found at http sourceforge net apps mediawiki cdk index php title ChemPaint TOXTREE USER MANUAL date a general threshold or a threshold developed in relation to toxicological data or structural information Thresholds based on structural information have typically been developed by the principles established by Cramer Chemicals are divided into three structural classes based on a decision tree This comprises some 33 structural rules and places evaluated compounds into one of three classes
16. urceforge net start html Exercise 3 Batch processing When dealing with large datasets more than 1000 molecules Toxtree should be used in batch processing mode It can be accessed through the File Batch processing menu Users are invited to select the input and output files Supported types are CSV TXT and SDF before starting the batch processing The batch can be paused 2 EINECS lookup requires Remote lookup enabled please consult page 3 on how to enable the remote queries TOXTREE USER MANUAL or aborted upon user request Batch configuration state can be saved and loaded at a later time In case of unexpected interruption e g power failure hardware failure operating system failure etc the batch job can be continued from the last previously fully processed record In order to achieve this the interrupted batch configuration should be loaded either from a user specified file or from the system TEMP folder where it is automatically stored if the user has not specified a file 1 change the decision tree used in the estimation through the Toxtree MethodP Select decision tree menu Select In vitro mutagenicity Ames test by ISS 2 Download the SDF file Benchmark Data Set for In Silico Prediction of Ames Mutagenicity from http doc ml tu berlin de toxbenchmark tox benchmark N6512 sdf 3 consult the decision tree accessible through the Toxtree Method View decision tree menu 4 classify
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