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CARLSBAD manual - University of New Mexico

1. a C340193 3 014790 CASP8 HUMAN CctecccctC 0 NNC O C2IC n 8041 2 4 cicdsct CNc2csO nH en2 C330439 4 1614790 CASP8 HUMAN CC CioNC CC 0 0X 0 o C147547 10 014790 CASP8 HUMAN c1cc2c ec INC O CCCIC O C C246680 3 014790 CASP8 HUMAN c1cce e ct C 0 NC2CC CCC3 A C AUR w o C291853 5 014790 CASP8 HUMAN CC C CC C sO NC1CC sOJOC y jo j Q S C341352 3 014790 CASP8 HUMAN ctcco cct C s0NC2CSCCN C2 o s c 3142 277 16 ctceeec1 c2 C CCC2 C192527 4 1014790 CASP8 HUMAN CCCC O C CC 0 ONC O C j 243234 4 014790 CASP8 HUMAN CCC CCXC sONC C C C C SO C330435 ig 014790 CASP8 HUMAN Teceecen cyencc 0 ciccr c330430 147547 Node Attribute Browser Edge Attribute Browser Network Attribute Browser Loaded 285 compounds 73 scaffolds 14 MCES Note This filter may take several minutes to compute and while it is doing so you will see new edges drawn and subsequently erased 24 ii Select structural class Now that your network has been rearranged with Apply force directed similarity weighted layout you might want to use the Select structural class tool to highlight specific structures This tool can be used at anytime to select either scaffolds MCESs or compounds separately or in combination In the screenshot below we have chosen to select scaffolds and compounds to highlight how the previous tool Apply force directed similar
2. can be found in the Merging CARLSBAD Networks section of this manual 14 the Import Network window top left will appear By clicking the Select button the Import Network Files window middle will appear allowing you to chose the file you downloaded from SNAKE Finally after selecting your file you will see the Import Network window bottom right again with the file extension Now you can click Import and File Edit View Select Layout Plugins Help Ba a amp Q8 s 9 5 9 Data Source Type Local Remote URL Please select a network fle Options snake PZQ 1 snake Rosig snake Rosig snake Rosigl snake JAAP _ smake_XIAP_ 7 snake PZQ FK Computer snake PZQ FKBPIA clccc cel C c2eccec2 C I3 L Fie name snake_Caspase_8_201 Qpen TAG Files oftype Al network files xml rdf onl om xgmmi nnf sf sbm v Cancel Import Network File Data Source Type Local Remote URL C Users jhines 18 Downloads snake Caspase 8 20120220 xgmml Select Import Cancel Browser Edge Attribute Browser Network Tip As you can see here naming your file in SNAKE is important to keeping your network files organized as you might be downloading multiple files from SNAKE In addition you must remember to name your file before hitting the search button in order for your filename to appear in the file you download 15 the Loading Network
3. cpd2scat 173176 pp 1713 33301020 acit 8 C246699 pp 4367 epa2scat 330423 pp 5864 epd2scaf C281853 pp T713 5 032452 acety 8 C2456679 pp T713 5 102372 aceaty 8 C123994 pp M86884 epd2m C246704 pp 585192 pd2scaf 153300 pp 1713 81113509 adMy 8 c Node Attribute Browser Edge Attribute Browser Network Attribute Browser Loaded 41 compounds 458 scaffolds 70 MCES After selecting some or all edges you will see edge attributes in the Data Panel at the bottom please see the Glossary at the end of this manual for specific definitions Note Like the node attributes the SNAKE file you downloaded contains additional edge attributes that can be seen by the same methods as were previously described for viewing additional node attributes 20 e Using the CARLSBAD plugin options Filtering tools In the CARLSBAD plugin you will find three Filtering Tools that can help you refine your network analysis These filters can be used separately or in combination However it is important to note that if using filters in combination you should apply the filters in the order they appear i Remove unmergeable CCPs This filter removes scaffolds and MCESs that are only associated with compounds in the current network That means the CCPs removed have no association with any other compounds from the CARLSBAD database and therefore cannot be used to find new
4. Attribute Expression Matrix Y YY oO vamp Propet Fe Import attributes from Biomart zd Load CARLSBAD network from SNAKE Merge CARLSBAD networks M C281851 ci Import Attributes from NCBI Entrez Gene 3 Li T Oves 5105852 5 6 132539 OO 340190 243230 7 s pooc2 c2cco ec2c Pa z 1014790 CASPS_ HUMAN XZCTIC SU NUT M 5 11014790 CASP8 HUMAN Tec O NC1CC 0 0 Die 4 1014790 CASP8 HUMAN CC C C C CONC CC 0 0 C Q a 5 1014790 Caspe Human 8 CC C CC C 20 NC1CC 35 19 jn 4 CICc2c3ACICCNIC 0 CCC2 can C197578 Node Attrbute Browser Edoe Atbibute Browser Network Attribute Browser i Losded 285 compounds 73 scaffolds 14 MCES e Next go to the VizMapper tab to the left of the CARLSBAD tab in the Control Panel You will see that the CARLSBAD visual style is selected however to apply the new style that you downloaded you must first choose another style i e Minimal and then select the CARLSBAD Visual style again 39 cytoxcape Desktop New Session ii File Edit View Select Layout Plugins S Bla Q a BG Fy Sy e L Control Panel Caspase 820120220 g Network Viepper CARLSBAD Editor Fiters Current Visual Style Visual Mapping Browser gi m Node Visual Mapping B I Node Color has nested netw
5. Q Q 689336 M66850 EDBBS S E we 1D valsti dass confidence 29 o C17572 M45023 CH 17572 pp T58 6 481486 activity o D eme C17572 pp T57 6 602059 activity s C17565 pp T57 7 244125 activity 17565 pp T58 7 3279 activity 17572 pp T31 74559 activity EN CT7565 pp T247 75086 activity 17572 pp T30 7 5229 activity 17565 pp T31 7 7447 activity 17565 pp T30 7 9586 activity EATEGE imni 44E adiac C470412 s9115 Node Attribute Browser Edge Attribute Browser Network Attribute Browser Loaded 4 compounds 1 scaffolds 3 MCES v eee e Mestres J Seifert S A and Oprea T I 2011 Linking Pharmacology to Clinical Reports Cyclobenzaprine and Its Possible Association With Serotonin Syndrome Clinical Pharmacology amp Therapeutics 90 662 665 37 7 Appendix 11 Applying Different Visual Styles to a CARLSBAD Network It is possible to alter the visual style of your network by changing the settings in the VizMapper tab in the Control Panel However to facilitate this process we have designed Vizmap Property Files that you can use to enhance your network view e Toaccomplish this simply download the Vizmap Property File from the CARLSBAD website carlsbad health unm edu This file can be found in the Downloads section of the CARLSBAD Community link on the homepage car
6. 0 PREAMBLE The purpose of this License is to make a manual textbook or other functional and useful document free in the sense of freedom to assure everyone the effective freedom to copy and redistribute it with or without modifying it either commercially or noncommercially Secondarily this License preserves for the author and publisher a way to get credit for their work while not being considered responsible for modifications made by others This License is a kind of copyleft which means that derivative works of the document must themselves be free in the same sense It complements the GNU General Public License which is a copyleft license designed for free software We have designed this License in order to use it for manuals for free software because free software needs free documentation a free program should come with manuals providing the same freedoms that the software does But this License is not limited to software manuals it can be used for any textual work regardless of subject matter or whether it is published as a printed book We recommend this License principally for works whose purpose is instruction or reference 1 APPLICABILITY AND DEFINITIONS This License applies to any manual or other work in any medium that contains a notice placed by the copyright holder saying it can be distributed under the terms of this License Such a notice grants a world wide royalty free license unlimited in duration to use that wo
7. 1014790 CASP8 HUMAN etcecct OCC2CCCN2S 0 1 id 80336 1 4 eten c 0 ent CC ONCC OO 599363 1 15 10 l Clec eec1C2CCCC2 OCC 0 st25066 1 i 14 I eee ve 7 132521 5132535 Node Attribute Browser Ease Atvtute Browser Network Atrbute ronse Loaded 411 compounds 488 scaffolds 70 MCES Note To improve the speed of this filter ensure you don t have any nodes selected when applying the filter as Cytoscape will attempt to continuously regenerate structural depictions in the Control Panel If this happens it will not harm anything but it may take a few moments longer to process 21 ii Remove promiscuous compounds This filter provides a user defined option for the Target Degree an attribute providing information as to the number of targets a CCP or compound relates to in the entire CARLSBAD database as opposed to just the targets in the file downloaded from SNAKE File Ede View Select Layout Pupm Help eg dana maig B Control Panel Tg meteor vattapoer 7 Editor Piers CARDO Yet site query a m o Search C269454 seers Data Panel v ag v V vx IBDEB Ox ol m dh aie uL nci d deg cd dept Targefumesiat mars D rest nae a o 5 1014790 CaSP8 cient g 5 1014799 CASPS ca i 5 1014790 CASP Caesa i i T6 1 sus p cones s 1014790 CASS 209456 D 1014790 CASPS C196 5 i Orcera e TOORE Mannes l0 8 5 1 NT s00 Iocs
8. M6078 0 l 4 1014790 CASPS CMDM NA 97 338 1 924 D Q L gt 5 1014730 CAPE onsas i 3 1014790 CASPE c232516 LAO 3 1014790 CASPE 328024 NA 5 1014790 CAPS casa N aa 5 1014790 GASPS n xieoze node armenn Bronse Edge Atribut Browser Veteork Arvbute Browser seset 45 cometan 8 scelti 22 NCES Note You may notice that this filter can remove compounds and CCPs despite the fact the filter says it s for Promiscuous compounds This is because CCPs that only associate with compound s that are removed will also be removed This is a convenient feature of this filter as well as the next filter we will use Remove specified activity edges because it not only removes those nodes which were defined by the filter but it also removes the disconnected nodes or those CCPs that only connected to the target through compounds which were removed 22 iii Remove specified activity edges This filter provides user defined options such as minimum activity which is a bioactivity attribute converted to log molar so that below 5 0 is the same as bioactivities above 10 uM In addition there is a box that is checked On occasion a compound may not have a specific known bioactivity for the target and by checking this box the default selection those compounds will remain in your network Select fiter parameters Minimum activity 5 0 Keep missing val std edges Iy Data Panel r3 A A 2 O u
9. To install Cytoscape go to the Cytoscape website at www cytoscape org download html and follow the download instructions version 2 8 2 or above e Obtaining a ChemAxon license In order to obtain a ChemAxon license you must i decide which type of license to request ii request the license and iii follow standard license installation procedures This information can be found at www chemaxon com my chemaxon my academic license e Installing the ChemAxon license Once you have obtained a ChemAxon license copy the retrieved file license cxl to one of the following directories according to the operating system on your machine i Windows7 C Users your_username chemaxon ii UNIX home your_username chemaxon iii Apple e SHOME your username chemaxon o Substitute SHOME with the path to your home folder Note You may have to create the directory yourself e Installing a Java Virtual Machine In addition we recommend that you ensure your computer is equipped as a Java Virtual Machine SE 6 Update 33 JRE or recent series 6 JRE is recommended Java updates can be found at www oracle com technetwork java javase downloads jre6 downloads 1637595 html e Loading the CARLSBAD plugin to Cytoscape After installing Cytoscape you will need to install the CARLSBAD plugin by launching Cytoscape going to the Plugins menu in Cytoscape and selecting Manage Plugins as depicted in the screenshot below This will launch
10. default A C Y network summan 31 CARLSBAD ID C790457 was identified as 2 2 3 dihydro 1 4 benzodioxin 2 yl 4 3 ethoxyphenyl thiazole in SciFinder We can see there is only one reference to the molecule and it is for a patent that was filed in 2009 pertaining to lifespan altering compounds This is interesting since we know our target Caspase 8 plays both a critical role in apoptosis and autophagy two processes that could be directly linked to the aging process X Aga KMF Ale Chem Get Get ep Get ag Get k Links Reference Detail Substances Reactions Cited Citing ae 0 Tags 0 Comments E Unk Save Pit Export o 7 Return Patent Information Method using lifespan altering compounds for altering the lifespan of eukaryotic organisms and screening for Jun 25 2009 such compounds US 20090163545 AL By Goldfarb David Scott Assignee University of Rochester USA Application The invention discloses a method for altering the lifespan of a eukaryotic organism The method comprises the steps of providing a lifespan altering compd Dec 22 2008 and administering an effective amt of the compd to a eukaryotic organism such that the lifespan of the organism is altered In one embodiment the US 2008 341615 compd is identified using the DeaD assay This abstr record is one of 20 records for this document necessitated by the large no of index entries required to fully i
11. New Mexico Chief Tudor I Oprea MD PhD Albuquerque NM 87131 USA Powered by TA amp ME Gael we Snare tia 1o na ten ChemAxonChemAxon Ltd SciTouch Cooperation and commitment to CRX e rosse D EE CDK project 34 i BadApple This tool will help provide additional promiscuity filtering Simply paste one or more SMILES directly from the CARLSBAD plugin into the field on the left of the screen and select the button submit molecule s The structures that pass the promiscuity filter will be highlighted in green with the lower pScores see values in the second column of output being less promiscuous BADAPPLE Promiscuity Analysis Output mols in 17 a lols sec Bptcoe nie E sip oec walk n dleanioso 1 few o o o ow o o o f ewpSsoe ciecc2c el C 0 C 0 NC2 0 eLece cc1 COC O NGC mO NGC O NCC O CO elece2z c1 cenc2c O NCSCCeCCCACOCCHACS t e1ecc cc1 OCC2CCCN28 O 0 e3eec c 63 C eleceze el C m0 C O N2 c nan ciccc2c ci CCNC2 lt B _ downioad badappie_out_csv bd 1 2 KB ChemAxon Ltd 35 ii SmartsFilter This tool will help provide filtering based on reactivity Simply paste one or more compound node SMILES directly from the CARLSBAD plugin into the field on the left of the screen select at least one filter from the middle window pane as you can see Oprea is the only filter selected in the screenshot below and select the button run smartsfilter Y
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14. ciccc2c c1 CNC2 1 om a srre 2 9 cienenctOCC2CCCN2 i 0 RM 576502 1 5 eecc cc1 CN2c3ccc co3C 0 C2 0 S 0 0 i 1 g a 76501 2 45 etec2e cc1S 0 0 N3CCOCC3 C 0 C 0 _ E Oo S76500 3 5 ctcoc cct CN2c3cod cc3C 0 C2 0 S 0X 0 i z C269456 876500 7 Node Attribute Browser Edge Attribute Browser Network Attribute Browser Loaded 403 compounds 442 scaffolds 74 MCES After selecting some or all nodes you will see structural depiction in the Control Panel left and node attributes in the Data Panel bottom Note In Cytoscape target nodes are represented by octagons compounds by squares scaffolds by diamonds and MCESs by hexagons 17 The attributes in the Data Panel that load automatically after importing a file are a subset of all the CARLSBAD attributes contained in the file you downloaded from SNAKE The entire set of attributes can be accessed in two ways To access all the attribute information of a specific node you can right click on a node in the Network View Panel and select the Show CARLSBAD info option which will then reveal a pop up window containing all the attribute information for that node In addition CD Cytoscape Desk m x File Edt View Select Layout Plugins Help amp EQ2QnQa OB O 8 lt B Control Panet ERG 8 201202 Toles fg Network vastapper CARLSBAD Editor Fiters Input structure query Depict chemical str
15. i HM 295 P55210 712 432 i 014790 T942 664 ji 109Y5Y4 Node Attribute Browser Edge Attribute Browser Network Attribute Browser The newly merged compounds are potential lead compounds however further research should be conducted before concluding they are definitely leads for the target of interest In addition it should be recognized that we only grew one of 70 CCPs here so continuing the merging process as described in this section will likely lead to more potential lead compounds and even some drugs that might be potentially repurposed Note Compounds that are known drugs are tagged with the node attribute is_drug and can be identified easily in CARLSBAD This manual and tutorial should provide a researcher with the necessary tools to quickly develop a logical and creative hypothesis However further research should be undertaken before beginning experimentation Some of the steps that might be undertaken are discussed further in the subsequent section Next Steps 30 5 Next Steps The CARLSBAD platform provides researchers with the ability to generate novel hypotheses pertaining to the relationships between biological targets chemical compounds and their common chemical patterns CCPs Hypothesis development is a highly personal and creative process beginning with a well defined question The powerful network theory and algorithms behind CARLSBAD can help guide resea
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18. the Manage Plugins pop up window where you can expand the Online data import subtree by clicking on the next the folder icon select the CARLSBAD v 1 1 plugin highlighted below and click the Install button CARLSBAD Version 1 1 Category Online data import Description CARLSBAD Released By The installation process will take several minutes Once installed click the Close button and you are now ready to begin using the CARLSBAD plugin to Cytoscape a process that will begin with a subnet query in SNAKE which is described in the next section 2 SNAKE SubNet Application Kit and Extractor for CARLSBAD SNAKE is a web based tool where you can perform target or compound based queries After performing your query SNAKE delivers target results for your network an option to view your network with Cytoscape Web and the ability to download a network file that can be imported into Cytoscape for advanced network visualization and analysis with the CARLSBAD plugin To begin using SNAKE please apply for a CARLSBAD user group license offered free for academic and non commercial usage at carlsbad health unm edu cgi bin cb_user_app cgi e Getting familiar with SNAKE SNAKE can be accessed through the CARLSBAD homepage at carlsbad health unm edu or via carlsbad health unm edu tomcat biocomp snake Once the web page is loaded you will notice the target query options in the left box and
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20. to the number of compounds another node may be associated with in the current network deg_tgt The number of targets another node i e Scaffold MCES or Compound is associated with in the CARLSBAD database which may be in contrast to the number of targets another node may be associated with in the current network Depict Chemistry A way to view the chemical structure of a compound or common chemical pattern CCP in the selected nodes Disconnected Node A node that is not connected via an edge to any other nodes Edges Connections relations between two nodes represented by lines in CARLSBAD Edge Attribute Browser A tab at the bottom of the Data Panel specific to edge attributes Identifier A common ID that identifies a biological target such as a protein or gene i e an EC number ChEMBL ID an Entrez Gene ID an NCBI GI number a RefSeq ID a Uniprot ID etc Lead Compound A compound that has a biological activity for a target and can be used as a starting point for chemical modifications that may lead to drug development MCES Maximum Common Edge Substructure An algorithm for identifying common chemical patterns Sometimes referred to along with a scaffold as a CCP Network Any set of nodes and edges Network growth or expansion A term used to describe what happens to an initial network when another network is merged with it Network View Panel A panel towards the upper right of the screen in Cytos
21. total edges 9517 7 Full ICE rel III AltName FulleProtease ICH 3 AltName Full Protease TY Contains RecName Full Cag aspase 6 subunit pli Flags ICE LAP3 Conta RecName Full Caspase 7 human enzyme Mch 5 AltName FADD honol d 3 11ke ted ced 3 homolog Short MACH Contains RecName Full Caspase 8 subunit p18 1046 Caspase 5 Full ICE like apop human enzyme sh 1553 Caspase 1 ie mouse enzyme Flags Precurs 1222 Caspase 10 Full Caspase 10 Apoptotic protease M ted death domain protein interleukin iB converting enzyme 2 Short FLICE2 AltName human enzyme like apoptotic prot 10 subunit p23 17 Flags a 5443 Caspase 4 aspase ll Short CASP i I RecName Full Caspase 4 pl0 Contains RecName Full Caspase 4 mouse enzyme 3443 Caspase 14 ise 14 Short CASP 14 EC 3 4 22 Contains RecName Full Caspase 14 subunit pl5 Contains RecName Full Caspase 14 subunit pl0 Flags Precursor buman enzyme 5784 caspase s kat protein 787 caspase 7 apoptosis pir human protein related cysteine peptidase download targets CSV 300 3 KB e Cytoscape Web Cytoscape Web offers network visualization as well as additional attribute information and structural depiction which can be obtained by selecting a node Below is a network depiction generated using the view subnet wit
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23. window top will appear during the importing process Select Close and the import process will finish and display the Parse SMILES node attribute window bottom Wy cosa Desay Siew Session i E Ww EN NF s v cei nen F e Edt View Select Layout Plugin Help pap nica PL TL z QQkQ gp 9 5 4 gg lli Corm Parat 2 Cpu 1 20120202 h vapper Editor Pitery CAR SEAL Simse sexo Options E Loading Network x cu a Description Loading Network Status Successfully loaded network from snake Caspase 8 20121212 xgmml Network contains 920 nodes and 1 791 edges Network is under 10000 nodes A view has been created automatically Parse SMILES node attribute Data P Cose Description Parse SMILES node attribute HORE deg d des t Targeturesust a us Status Parsed 403 compounds 442 scaffolds 74 MCES mh ser tage Kiste Browser Wateork Atv bute Browser amp Tip After closing the Parse SMILES node attribute window you will likely want to maximize the network view by clicking the square expand window button above the network depicted and then selecting the 1 1 Magnifying Glass button highlighted at the top of the screen in order to maximize and center the network view 16 e CARLSBAD Node Attributes and Cytoscape Viewing Panels There are three panels in Cytoscape the Control Panel le
24. 0 C CC CXC ctcc 2ncan c c2n1 CCC C ONC CC O O C Cetecce ct C O NNC 0 C2 CC C CC C O NC1CC O O CC CIC CL O NC CC 0 0 C CC CICCC eOINC1CC 0 O OszC1N Cc2ccocc2 c2e0c oc2C etec2e3e c1 cCN3C 0 cCC2 And the new VizMapper style you downloaded will be applied NEMORE X Select Layout Plugins Help Sala aa ald 55g e Control Panel A Gl Caspese 8 20120220 dg Network vaMapper CARLSBAD Input structure query Substuchre v Search Options Data Panel EDBES 8 p D ees I deg tot Targettismestist smarts Loaded 285 compounds 73 scaffolds 14 MCES Node Attrbute Browser Edge Attrbute Browser Network Attribute Browser 40 8 Glossary Apply force directed similarity weighted layout A CARLSBAD plugin tool that contains options allowing the user to rearrange their network so that chosen node classes are grouped based on structural similarity and edge distance between the target s and compound s is related to the affinity the compound s have for the target s This is accomplished by changing the distance of compound edges connected to targets and CCPs based upon Tanimoto similarity values O 1 In addition Compound Target edges which have val std activities are mapped to Tanimoto values val std gt 8 gt 1 val std lt 8 and val std gt 5 gt val std 10 val std lt 5 gt 0 1 Attribute A no
25. 331 T106 7 920 ser Edge Attribute Browser Network Attrbute Browser CARLSBAD is offered FREE for academic and non commercial research In order to APPLY for CARLSBAD user group membership carlsbad health unm edu cgi bin cb_user_app cgi obtain system access access supporting documentation and downloads as well as learn more about the CARLSBAD platform and UNM s Translational Informatics Division please visit the CARLSBAD website at carlsbad health unm edu Questions can be answered by emailing CARLSBAD at info carlsbad poblano health unm edu CARLSBAD was developed at the University of New Mexico School of Medicine Translational Informatics Division by Tudor Oprea Cristian Bologa Stephen Mathias Oleg Ursu Jeremy Yang Gergely Zahoranszky Kohalmi Jerome Abear and Jarrett Hines Kay and funded by NIH grant GM095952 1 Installati TABLE OF CONTENTS on and Downloading Procedures 5 Obtaining a CARLSBAD user group license Installing Cytoscape Obtaining and Installing a ChemAxon license Loading the CARLSBAD plugin to Cytoscape 2 SNAKE SubNet Application Kit and Extractor for CARLSBAD 7 Getting familiar with SNAKE Query Options Result Options Cytoscape Web Additional Options 3 The CARLSBAD Plugin for Cytoscape 13 Importing a file downloaded from SNAKE into the CARLSBAD plugin for Cytoscape CARLSBAD Node Attributes and Cytoscape Viewing Panels CARLSBAD Edge Attributes Using the CARLSBAD plugin op
26. AD Editor Fiters Input structure query Sese un Search Q d 51262198 383812 OD Forum 5132526 520324 i j on y r Q avg C ash C328721 C330419 Y V name C330419 3 e r En 20307 520315 ff ne Loaded 411 compounds 458 scaficids 70 MCES ETT us i a 3 E 19 e CARLSBAD Edge Attributes So far we have been learning about accessing node attributes however important information such as bioactivity is contained in the edges To access edge attributes you will need to select edges and then chose the Edge Attribute Browser tab at the bottom of the Data Panel next to the Node Attribute Browser tab that has been selected in the previous screenshots in this section of the manual You can select all edges by either hitting Alt A or going to the Select drop down menu at the top and choosing Edges This latter menu option provides for further edge selection capabilities CY Cytoscape Desktop File Edit View Select Layout Plugins Help S BiA aA a E Bg e Control Panel Efa Capres N1020 Jg Network visMapper CARLSBAD Editor Fiters Input structure query Options Data Panel EJ E DB B foo E D vasa dass cofdexe C246686 pp 85173 epdascat 340206 pp 132547 epa2scat 246703 pp 585211 epd2scaf C246700 pp S85215 epa2scaf C340202 pp 132542 epd2scaf 197559 pp 2234 cpd2scaf 246705 pp 585222
27. CARLSBAD User Manual amp Tutorial The Power to Explore Biological Networks via Chemical Patterns carlsbad health unm edu Copyright C 2012 Jarrett Hines Kay Permission is granted to copy distribute and or modify this document under the terms of the GNU Free Documentation License Version 1 3 or later published by the Free Software Foundation with no Invariant Sections with the Front Cover Text being CARLSBAD User Manual and no Back Cover Texts A copy of the license is included in the section entitled GNU Free Documentation License of this manual This is a reference manual for the CARLSBAD platform which consists of a database a database query tool called SNAKE and a plugin to Cytoscape for network visualization and analysis The manual is constructed around a tutorial to help users better understand CARLSBADs capabilities and how the system can be utilized for hypothesis generation The CARLSBAD platform is free for academic and non commercial usage however you must apply for a User License carlsbad health unm edu cgi bin cb_user_app cgi and this can take several days In order for you to test the platform we have made the two files that the tutorial uses available on the CARLSBAD project homepage carlsbad health unm edu These files can be obtained by clicking the CARLSBAD Community link and downloading the two CARLSBAD tutorial XGMML files under the Downloads heading In addition there is a glossary of definitions tha
28. OMBAT PK Bioactivity Databases for Lead and Drug Discovery In Chemical Biology From Small Molecules to Systems Biology and Drug Design Schreiber S L Kapoor T M and Wess G Eds Wiley VCH Verlag GmbH Weinheim Germany pp 760 786 Raymond J W Gardiner E J and Willett P 2002 RASCAL Calculation of graph similarity using maximum common edge subgraphs Computer Journal 45 631 644 Roth B L et al 2000 The Multiplicity of Serotonin Receptors Uselessly Diverse Molecules or an Embarrassment of Riches Neuroscientist 6 252 262 Shannon P et al En Cytoscape A software environment for integrated models of biomolecular interaction networks Genome Research 13 2498 2504 Sharman J L et al 2011 IUPHAR DB new receptors and tools for easy searching and visualization of pharmacological data Nucl Acids Res 39 D534 D538 Yang J J 2011 UNM Biocomp hscaf Java library for HierS chemical scaffolds Google Code open source project http code google com p unm biocomp hscaf Wilkens S J Janes J J and Su A I 2004 Hiers Hierarchical scaffold clustering Abstracts of Papers of the American Chemical Society 228 U368 U368 44 10 GNU Free Documentation License Version 1 3 3 November 2008 Copyright 2000 2001 2002 2007 2008 Free Software Foundation Inc lt http fsf org gt Everyone is permitted to copy and distribute verbatim copies of this license document but changing it is not allowed
29. Refine Times Cited 31 from Web of Science Parne 03 View abstract gt Subject Areas E 3 Title P53 mediated cell cycle arrest and apoptosis through a caspase 3 independent but caspase 9 dependent pathway in gt Authors oridonin treated MCF 7 human breast cancer cells Author s Cui Qiao Yu Jing ua Wu Jin nan et al gt Group Authors Source ACTA PHARMACOLOGICA SINICA Volume 28 Issue 7 Pages 1057 1066 DOI 10 11119 1745 7254 2007 00588 x Published JUL 2007 rE Times Cited 23 from Web of Science View abstract gt Source Titles gt Book Series Titles E 4 Tite DEVD NucView488 a novel class of enzyme substrates for real time detection of caspase 3 activity in live cells Author s Cen Hui Mao Fei Aronchik Ida et al gt Publication Years Source FASEB JOURNAL Volume 22 Issue 7 Pages 2243 2252 DOI 10 1096 1 07 099234 Published JUL 2008 Times Cited 17 from Web of Science UNM Fu Text amp View abstract gt Funding Agencies gt u E 5 Title New Potential Anti Cancer Agents Synergize With Bortezomib and ABT 737 Against Prostate Cancer Author s Pandit Bulbul Gartel Andrei L gt Countries Territories Source PROSTATE Volume 70 Issue 8 Pages 825 833 DOI 10 1002 pros 21116 Published JUN 1 2010 Times Cited 9 from Web of Science For advanced refine options use UN MFull Text g View abstract Analyze Results 6 ritie Mechanism of apoptosis induced by a newly synthesized derivative of macro
30. SNAKE into the CARLSBAD plugin for Cytoscape as well as familiarize you with the tools that CARLSBAD provides for network visualization and analysis It will do this by taking you through a tutorial example that if you wish to follow will require you to download the human Caspase 8 target file from SNAKE see screenshot on previous page Importing a file downloaded from SNAKE into the CARLSBAD plugin for Cytoscape Once you have performed a query with SNAKE you can import the file you downloaded into the CARLSBAD plugin for Cytoscape However before importing you should familiarize yourself with the location of the CARLSBAD tools available in Cytoscape This is a simple task as there are two menus you will use for accessing the powerful functions of the CARLSBAD plugin CARLSBADs analysis tools can be found in the Plugins menu at the top of the Cytoscape window as depicted here Cytoscape Desktop New Session File Edit View Select Layout Plugins Help ele ao Control Panel Tg Network VizMapper Edito Input structure query Substructure Manage Plugins Update Plugins Install Plugin from File Advanced Network Merge Carlsbad Depict chemistry Network Analysis Connect structural patterns to targets Network Modifications directed similarity weighted layout Data Panel ov o BOKE D _deo_cpd 5 fo 5 NI deg tot TargetNamestist is drug smiles smarts Node Attrib
31. al patterns and activity values After selecting the Apply force directed similarity weighted layout option a window will appear allowing you to select which attribute relationship s you would like to favor when rearranging your network All choices refer to structures so that nodes will cluster based on how structurally similar they are to each other except for the Compound Target option which refers to bioactivities such that the greater the affinity a compound has for a target the closer it will be to that target after the network rearrangement File Edt View Select Layout Plugins Help e a Q Q a Manage Plugins Update Plugins Control Panel Install Plugin from File Tg Network vattagper CARL XEM EU Advanced Network Merge Carlsbad Depict chemistry OT Network Analysis Connect structural patterns to targets NA Substructure Network Modifications Apply force directed similarity weighted layout Filtering tools pas prone Select structural class n by sQ D ayy j DA p 6330426 78282 5 D ma C246681 5 V Compound Target V Scaffold Scaffold Zw V MCES MCES JQ Data Panel 2 E3 ovo l WN Ovo p se depict C330420 4 1014790 CASP8 HUMAN T CCC C 0 NC CC 0 O C 0 78282 5 014790 CASP8_HUMAN Clece ect ON2c3cce cc3C 0 C C246681 3 014790 CASP8 HUMAN ctec ec c1 6C 0 NC2CC CC ES eos C246695 3 014790 CASP8 HUMAN etece ect C ONC2CCCCC3C
32. all users should limit use to 5000 molecules per day All usage is logged and overuse may result in client IP blocking For Special requests such as high volume jobs and collaboration inquiries contact the Division of Biocomputing Input file sizes Note that these web apps given typical network throughput are impractical for large input files In most cases the app restricts input file sizes In general files in excess of a few thousand lines e g 2000 smiles should not be uploaded For help contact Jeremy Yang 35yang8salud unm edu For poster describing these webapps click here badapple bioactivity datamining associative promiscuity pattern learning engine ChemAxon clustermols Cgi duster molecular datasets Mesa OpenEye Scitouch Convert convert mot formats ChemAxon depict sepict molecules ChemAxon drug likeness nos using DRUGS ACD fragments frequencies ChemAxon IPHACE inecrative navigation in pharmacological space ChemAxon moledit jcp Cgi pojecuiar editor utiity COK molprops Ob Cgi moiecutar properties and aggregate stats OpenBabel Scitouch Gnuplot Gnuplot Py rockit cgi Roc curve plotter R ROCR RPy Gnuplot Gnuplot Py SIM2 25 sim arity ChemAxon smartsfilter smars filtering with built in Glaxo Blake and Oprea smarts sets ChemAxon Division of Biocomputing MSCH 6145 Dept of Biochemistry amp Molecular Biology Research Incubator Buiding Suite 170 School of Medicine 2703 Frontier NE University of New Mexico 1 University of
33. cape that depicts the network Node Attribute Browser A tab at the bottom of the Data Panel specific to node attributes Nodes A set of objects in a network i e Compounds Scaffolds MCES and Targets represented by shapes in CARLSBAD A node may have zero or any number of associated edges Remove promiscuous compounds A filter that removes compounds above a specified deg tgt 42 Remove specified activity edges A filter that removes edges below a defined val_std activity Remove unmergeable CCPs A filter that removes common chemical patterns CCP where the edges connected to the CCP in the network are equal to the deg cpd of that CCP In other words a filter that removes CCPs with no potential for network growth Repurposed Drug A new indication for a known drug Scaffold A means of identifying common chemical patterns via a collection of ring ring systems in a compound and linkers which connect them Sometimes referred to along with an MCES as a CCP Select structural class A tool that allows you to select the specific structural class of nodes in a network i e compounds scaffolds or MCESs SMARTS Line notation for specifying chemical substructure patterns SMILES Line notation for specifying chemical structures SNAKE SubNet Application Kit and Extractor A web app for selecting a subset sub network of the global CARLSBAD interaction network and either 1 exporting that sub net XGMML fo
34. cec2 c2cee ce2C1 0 S 0 0 N 3640 157 107 il etecc ect CCNC O OCc2ccccc2 i I S859 31 29 i ctece cct1 S 0Y O NCc2cccs2 i fi N d S200 590 296 0 etecc2e c1 0CCO2 eo I 6780 59 38 i exe 1 S 0X O NCc2cccon2 o s19759_ 2 EL ru croci O c2ccenca _ _ 0 P S268512 7 10 tener NC O CCC O Nc2ccc3c c2 C 0 i S 523465 34009 Node Attribute Browser Edge Attribute Browser Network Attribute Browser Loaded 0 compounds 57 scaffolds 13 MCES In addition we have removed the compounds in the network and arranged the nodes based on attribute similarities A depiction of this can be seen in the screenshot below and can be compared to the network we began with in the CARLSBAD Node Attributes and Cytoscape Viewing Panels section of this manual 27 4 Merging CARLSBAD Networks Network growth the ability to grow your current network based on the network of another node that is in your current network can be achieved in CARLSBAD by the merging of networks downloaded from SNAKE To do this we must generate a network file from SNAKE as we learned in the section SNAKE SubNet Application Kit and Extractor for CARLSBAD but for a node in the current network for which we are interested In this manual our current network is the Caspase 8 network that we have been working with and based on our analysis thus far we will choose a CCP to merge and thus grow this network e W
35. de edge property CARLSBAD Plugin A Cytoscape plugin developed specifically for use with the CARLSBAD system CCP Common Chemical Pattern A term used to group MCESs and Scaffolds together as they are different means to the same end common chemical patterns Compound CPD A small molecule or peptide that has the potential to modulate a target Connect structural patterns to targets A tool that connects the common chemical patterns CCP a compound is associated with directly to the target s by removing the compound nodes and creating a new edge directly to the target s Control Panel A panel towards the left of the screen in Cytoscape that depicts structures in the CARLSBAD plugin and provides further Cytoscape options such as network visualization tools and custom filters Current Network The network you are actively investigating To be contrasted to a network you might use to grow your current network Cytoscape Open source community based general purpose network analysis application with many domain specific plugins available Cytoscape Web A Flash plugin developed by the Cytoscape community for in browser network analysis Data Panel A panel towards the bottom of the screen in Cytoscape that depicts attribute information and allows sorting by attribute 41 deg_cpd The number of compounds another node i e scaffold MCES or target is associated with in the CARLSBAD database which may be in contrast
36. document and applying all the filters and tools described thus far we have now reduced the original Caspase 8 network which contained 403 compounds 442 scaffolds and 74 MCES down to just 57 scaffolds and 13 MCES that are all associated with compounds which have a minimum activity for the target of 5 0 log molar are mergeable a concept we will explore further in the next section and are not associated with compounds that are too promiscuous by our own definition fO Cytoscape Desktop New Session File Edit View Select Layout Plugins Help amp iueaewmea Sg a By P eg n i Control Panel Tg Network vieMapper Editor Fiters CARLSBAD Input structure query r7 Substructure r C Seach Options 1 2 S ddp fU C269456 C342314 3 a po Aa ia G DU C269493 pe p u En BOKE E 5E jy d C AA D deg cpd deg tot TargetNamestist smiles smarts UniProt name N Q S924 807 338 etecc cct Oc2ccccc2 n ji 0 D 382 587 262 i cicct cci 2cscn2 n S23465 9 4 il CACCN2C 0 CCCC O NZC1 i s m34009 3 8 i OCEO CCINCEO cTeso CNCe2ecc Oat T zd iia S921 441 295 1 cIcoclcc1 CCcZococc2 7 8 s7259 57 53 cicec cc1 C23CC4CC C2 CC C4 C3 o S257072 _ 3 6 etccc cc1 COC ONCC O NCC O NC2CCK T la 1214 594 356 Ciccc2cnccc2ct iil a m16035 16 5 i O CAN Ce2cc
37. e begin this process by first choosing a CCP in this case we will be using 58036 which also can be represented with SMILES c1ccc cc1 c2csc n2 C3COc4ccccc403 then querying SNAKE for the network based file associated with the chosen CCP by either querying the scaffold ID or using SMILES in the structure box of the compound query in SNAKE this process is discussed in the SNAKE SubNet Application Kit and Extractor for CARLSBAD section of this manual and finally downloading that file into Cytoscape with the CARLSBAD plugin by Cyroscape Deskop New fenore m LL H T Fir Ete Vien Select Layout Plugins Help 2 Gene Lod CARLSBAD network from SNAKE Merge CARLSBAD netwerts sat 515 348 Node armenn Browse Edge Attribute Browser Neteork Arr te Browser selecting the Merge CARLSBAD networks option from the File Import drop down menu Next we simply select the file as we previously did in the Importing a file downloaded from SNAKE into the CARLSBAD plugin for Cytoscape section of this manual 28 After merging networks you can see the new growth network highlighted in yellow the original TOI Caspase 8 highlighted in yellow octagon in the middle and the scaffold we grew highlighted in green Cytoscape Desktop New Session ss a TOS amp E amp amp X amp ag al P Sse B Control Panel E mega Tote fee fg Network VieMepper Editor Fiters CARLSBAD ies Inpu
38. equires Flash plugin mcesnodes 74 total nodes 920 activity edges 410 scaffold edges 1072 mces edges 316 total edges 1798 species type faman Jensen Finally there are some additional output options above the misc box such as n max targets which allow you to alter the amount of results returned in case of query truncation a warning that will appear if your search yields more than the default 100 targets Note This manual will describe CARLSBAD features in the context of a tutorial example that requires you to download the human Caspase 8 target file from SNAKE depicted above and import it into Cytoscape for analysis with the CARLSBAD plugin described in the preceding section Since CARLSBAD is an ongoing project it is possible that some of your results will vary slightly from the screenshots in this manual 12 3 The CARLSBAD Plugin for Cytoscape Cytoscape is an open source bioinformatics software platform that CARLSBAD is able to utilize via the plugin for powerful network visualization Combining these capabilities with CARLSBAD s powerful cheminformatics and pattern recognition algorithms will allow researchers to generate hypotheses involving the relationships between biological targets chemical compounds and their common chemical patterns CCPs This section will focus on how to import a file downloaded from
39. ething more static like SMILES SMARTS 32 Finally performing a literature search for thiazole and caspase in Web of Science reveals 13 articles one of which looks specifically at Caspase 8 depicted as the 6th result in the screenshot below and none of which involves the potential lead compound identified in this manual 2 Sev 7 Sf Analyze Resuts Refine Results s FM BB soveto LEndNifbWeb Endnote RefWorks ResearcherlD more options Gil Create Clason Report Search within results for m1 g p J Title p38 mitogen activated protein kinase dependent and independent intracellular signal transduction pathways leading to BS Author s Frasch SC Nick JA Fadok VA et al v Web of Science Categories _ Refine Source JOURNAL OF BIOLOGICAL CHEMISTRY Volume 273 Issue 14 Pages 8389 8397 DOI 10 1074 bc 273 14 8389 Published APR 3 1998 Mioncovosy 5 Times Cited 224 from Web of Science PHARMACOLOGY PHARMACY 5 gt Full Text 5 view abstract E BIOCHEMISTRY MOLECULAR BIOLOGY 3 E CHEMISTRY MEDICINAL 2 E 2 Tite Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression F CHEMISTRY MULTIDISCIPLINARY 2 Author s Kwok Jimmy M M Myatt Stephen S Marson Charles M et al more options values Source MOLECULAR CANCER THERAPEUTICS Volume 7 Issue 7 Pages 2022 2032 DOI 10 1158 1535 7163 MCT 08 0188 Published JUL 2008 Y e mo Document Types
40. f this License or any later version applies to it you have the option of following the terms and conditions either of that specified version or of any later version that has been published not as a draft by the Free Software Foundation If the Document does not specify a version number of this License you may choose any version ever published not as a draft by the Free Software Foundation If the Document specifies that a proxy can decide which future versions of this License can be used that proxy s public statement of acceptance of a version permanently authorizes you to choose that version for the Document 11 RELICENSING Massive Multiauthor Collaboration Site or MMC Site means any World Wide Web server that publishes copyrightable works and also provides prominent facilities for anybody to edit those works A public wiki that anybody can edit is an example of such a server A Massive Multiauthor Collaboration or MMC contained in the site means any set of copyrightable works thus published on the MMC site CC BY SA means the Creative Commons Attribution Share Alike 3 0 license published by Creative Commons Corporation a not for profit corporation with a principal place of business in San Francisco California as well as future copyleft versions of that license published by that same organization Incorporate means to publish or republish a Document in whole or in part as part of another Document An MMC is eligible for
41. ft the Data Panel bottom and the Network View Panel main window depicted with network containing yellow nodes below In the Network View Panel you can select all nodes by either hitting Ctrl A or going to the Select drop down menu at the top and choosing Nodes This latter menu option provides for further node selection capabilities Cytoscape Desktop New Session je File Edit View Select Layout Plugins Help B Search B amp amp Ba G9 aj E B s Control Panel E Te Network vizMapper Editor Fiters CARLSBAD Input structure query Sisene v C Options 1 2 Qr om 5249414 135631 3 a T d 5253197 c269441 5 s e Data Panel SOLU BOR Beem OY N D degcpd deg_tat smiles smarts TargetNamestist UniProt name zu o T712 432 814790 Caspase 8 E i Or s93398 2k _ c1ecelec1 C O NNC 0 C2CCCCC2 MM oO 1 3 S924 607 338 cicoc cct Oc2ccccc2 i 0 S921 441 205 ciccc cct CCc2ccccc2 i 0 pepe Soon S89132 6 5 ctcc2c cetS OY O N3CCCC3 C O C ON D i n s89131 8 5 cicc2dcDCCO CCON2C3dnHm3 1 0 si S86245 5 6 c1cec2c ct C O C O N2Cc3ccccn3 0 S859 31 29 c1ccc cc1 S 0 O NCc2cccs2 i u S847 210 35 ctenec O nH 1 0 0 sA o i 58290 69 43 cIccc cc1 OCC2CCCN2 0 deri AA OL 7891 190 142
42. g the latter be aware the CARLSBAD IDs change so it is recommended in your research to track structures by something more static like SMILES 29 tau We can see in the Data Panel towards the bottom of the screen with the Node Attribute Browser tab selected that there are three new compounds and five new targets that have been grown In the Data Panel you can see the names of all the targets Also the new compou nds are highlighted in green Cytoscape Desktop New Session Toy File Edit View Select Layout Plugins Help amp amp amp amp amp amp a E 3 D Ds di Control Panel E ii Merged Te Te es Ci temen vine ee ts iso Input structure query Substructure _ Search Options 790487 315405 Ogo rng C392341 558036 Loaded 3 compounds 57 scaffolds 13 MCES Data Panel E E BH De EN D deg cpd deg tot smiles smarts UniProt TargetNvemestist name ctocc2c cOCC O2 c3nc cs3 c4cccc e4 CIF i 392341 etoce2c c1 OCC O2 e3nc e s3 CC 0 0 c4cc _ i 790457 CCOctocen ct c2esc n2 C3COcdeccce403 T i P C315405 P42574 CASP3 O9Y5Y4 GPR44 014790 CASPS 42574 i Caspase 3 survival of motor neuron 2 centrome ras related protein Rab 9A Caspase 7 Caspase 8 Putative G protein coupled receptor 44 S58036 3 etece cct e2esc n2 C3COc4ccooc4O3 T149 1841 i T3657 5898 T3764 9142
43. h CytoscapeWeb button found in the Results section of SNAKE after performing a query see previous screenshot th unm edu merge edges v scaffold layout ForceDirected V smiles ctecc cc 1 CCC 0 N2CCCC2C O NC Ce3eccce3 C 0 NCCe4ccecc4 tgt labels default deg tgt 10 cpd labels default deg cpd 61 d 532983 network summary 10 Additional Options SNAKE provides a few additional options that can be found in the top right region of the SNAKE window The reset button clears all fields and can be useful when analyzing multiple networks there is a help button for assistance and there are selections for mode query type snake SubNet Application Kit amp Extractor for CARLSBAD mode 9 normal advanced help reset target query compound query misc exact sub name exact O sub Subnelfile CARLSBAD SubNec 20121 descr exact sub substructure graw query or enter smiles or smarts semen since Monday January 9 2012 times used 462 Thus far the screenshots of SNAKE have been for the normal query mode Below you can see some additional options available when selecting the advanced query mode in the top right part of the window Note When using SNAKE to generate a file for import into Cytoscape naming your file under the misc heading in SNAKE is highly recommended as it is easy to get confused as to which files you are w
44. h can be found in the drop down menu for type In the compound query box you can search by name name a drawn structure structure or SMILES SMARTS In addition you will notice the options exact and sub after entering text These allow you to narrow or broaden your search For example you can see in the previous screenshot that a search for casp short for caspase retrieves no results when exact is selected however SubNet Application Kit amp Extractor for CARLSBAD mode 9 normal advanced heip reset compound query misc exact sub name 9 exact C suh subnet lile CARLSBAD SubNez 20121212 7 verbose Dei ah Substructure TO o mete asuch Results extracted subnet target nodes 15 compound nodes 2361 scaffold nodes 2139 mces nodes total nodes activity edges scaffold edges mces edges total edges o MB Qi Web view subnet with CytoscapeWeb NOTE CytoscapeWeb requires Flash plugin Since total nodes 1000 Cytoscape Web not recommended By changing the option from exact to sub will allow you to broaden your search and as you can see from the extracted subnet in the Results above the same casp query performed as sub retrieved 15 targets Note In SNAKE s target q
45. hanges limited to the covers as long as they preserve the title of the Document and satisfy these conditions can be treated as verbatim copying in other respects If the required texts for either cover are too voluminous to fit legibly you should put the first ones listed as many as fit reasonably on the actual cover and continue the rest onto adjacent pages If you publish or distribute Opaque copies of the Document numbering more than 100 you must either include a machine readable Transparent copy along with each Opaque copy or state in or with each Opaque copy a computer network location from which the general network using public has access to download using public standard network protocols a complete Transparent copy of the Document free of added material If you use the latter option you must take reasonably prudent steps when you begin distribution of Opaque copies in quantity to ensure that this Transparent copy will remain thus accessible at the stated location until at least one year after the last time you distribute an Opaque copy directly or through your agents or retailers of that edition to the public It is requested but not required that you contact the authors of the Document well before redistributing any large number of copies to give them a chance to provide you with an updated version of the Document 4 MODIFICATIONS You may copy and distribute a Modified Version of the Document under the conditions of sections 2
46. he paper Mestres showed that cyclobenzaprine probably bound several serotonin receptors causing the syndrome We validated these findings with CARLSBAD by first performing a search for cyclobenzaprine in SNAKE which revealed an association in the CARLSBAD database with only one target DRD1 a dopamine receptor After importing the XGMML file into Cytoscape via the CARLSBAD plugins automated importing method Load CARLSBAD network from SNAKE the network revealed two CCPs associated with cyclobenzaprine Using the Merge CARLSBAD networks function to merge the cyclobenzaprine network with the networks of these CCPs revealed nine additional targets including two additional dopamine receptors two cytochrome P450s two enzymes and three serotonin receptors which were mentioned as likely being the causative agents of SS in Mestres s work Thus we were quickly able to predict off target side effects that matched literature using CARLSBAD r Help i e a Q Q a Manage Plugins ay rs RE gt B Update Plugins Control Panel Install Plugin from File 8 x lt 1e Network vizMapper CARL i ERU CEREEIEGEY Advanced Network Merge ud Carlsbad J Depict chemistry Network Analysis J Connect structural patterns to targets Substr Network Modifications Apply force directed similarity weighted layout Filtering tools o i Select structural class Q Q C17565 Me1166 obo m
47. implication that these Warranty Disclaimers may have is void and has no effect on the meaning of this License 2 VERBATIM COPYING You may copy and distribute the Document in any medium either commercially or noncommercially provided that this License the copyright notices and the license notice saying this License applies to the Document are reproduced in all copies and that you add no other conditions whatsoever to those of this License You may not use technical measures to obstruct or control the reading or further copying of the copies you make or distribute However you may accept compensation in exchange for copies If you distribute a large enough number of copies you must also follow the conditions in section 3 You may also lend copies under the same conditions stated above and you may publicly display copies 3 COPYING IN QUANTITY If you publish printed copies or copies in media that commonly have printed covers of the Document numbering more than 100 and the Document s license notice requires Cover Texts you must enclose the copies in covers that carry clearly and legibly all these Cover Texts Front Cover Texts on the front cover and Back Cover Texts on the back cover Both covers must also clearly and legibly identify you as the publisher of these copies The front cover must present the full title with all words of the title equally prominent and visible You may add other material on the covers in addition Copying with c
48. ity weighted layout rearranged the network Biciteccape Dico Den Seni File Edt Vere Select Layout Plugins Help DAAA aa DO y n R e 5 Control Panel a Jg netwo vattagper 7 banor riens CARLEAO bos structure query Sewrukae mo Seach L ES m Data Panel c A i Aih AAN BORSE om L OO HQ deed eset Tete E vert none Y O g jo14790 CASPS se MCGMICCRO OCIO _ Cms j 4 Tjo14790 Casha E CC 0 0 CI0 CCCcte css ii 307 38 rj 5624 i 3 OENE 232816 caaeeze caen 3 014790 CASPA 328024 r LI s jol4790 CASPa C269499 D za s j014790 CASPO C3ro607 Lp 587 262 s382 f 4 5 IIGMTSO CASPR C200408 JA 3 Tpata790 CASPA 232506 y 9 4 a 23465 el fa 01790 Casea C185047 1 7 4 jou7s0 CasPg Cua li Y Q 4a 14790 CASPa ic Ct85056 D 3 214799 CASPB cicccicct CNC C2 CIC HI C SO PW C2IC cues i eyroes sl nose amete Browser Edge Aitrbute Bronser Network Attribute Browser As you can see the nodes clustered in yellow on the right are scaffolds the nodes clustered in yellow in the center are the compounds and the nodes that remain unhighlighted at the bottom are MCESs 25 iii Connect structural patterns to targets This tool will remove the compounds in your network and connect the CCPs directly to the target When using Connect structural patterns to targets you will lose some attribute information such as the activity values since th
49. lete any section Entitled Endorsements Such a section may not be included in the Modified Version N Do not retitle any existing section to be Entitled Endorsements or to conflict in title with any Invariant Section e O Preserve any Warranty Disclaimers If the Modified Version includes new front matter sections or appendices that qualify as Secondary Sections and contain no material copied from the Document you may at your option designate some or all of these sections as invariant To do this add their titles to the list of Invariant Sections in the Modified Version s license notice These titles must be distinct from any other section titles You may add a section Entitled Endorsements provided it contains nothing but endorsements of your Modified Version by various parties for example statements of peer review or that the text has been approved by an organization as the authoritative definition of a standard You may add a passage of up to five words as a Front Cover Text and a passage of up to 25 words as a Back Cover Text to the end of the list of Cover Texts in the Modified Version Only one passage of Front Cover Text and one of Back Cover Text may be added by or through arrangements made by any one entity If the Document already includes a cover text for the same cover previously added by you or by arrangement made by the same entity you are acting on behalf of you may not add another but you may replace the old one on e
50. lsbad project homepage carisbad health unm edu A Division of Biocomputing Server Carlsbad documentation and information CARLSBAD Announcement March 9 2012 CARLSBAD User Manual HTML PDF with installation instructions CARLSBAD Communit CARLSBAD User Group Application Form for access credentials CARLSBAD Poster POF OpenEye CUP 13 3 5 2012 CARLSBAD Team Acknowledgements Applications running on this host CARLSBAD User Group access only e SNAKE SubNet Application Kit amp Extractor for CARLSBAD e CARLSBAD Web App Other pages of interest e Division of Biocomputing Homepage o Cytoscape Homepage e Cytoscape Web Homepage e Official floscape page for CARLSBAD Plugin NIH Project information page for CARLSBAD e d zx CARLSBAD Project UNM Division of Biocomputing 38 C117952 e After downloading the file go to the File menu in Cytoscape and select Import and Vizmap Property File Choose the file you downloaded from the CARLSBAD website in the pop up window and select the Open button Cytoscape Desktop Kun TNAM LIEU mnn it n mm se 8 2012022 Save Ctrles Save as Cte Shifts Bem Import gt Network Multiple File Types Ctrtel Export 1 Network from Table Text MS Excel Recently Opened 1 Network from Web Services Print Ctrl P Node Attributes Quit Cti Q Attribute from Table Text MS Excel Ontology and Annotation XX
51. mpound hypothesis into a potential for drug repurposing 33 e Additional Biocomputing Tools for Filtering In the previous part of this section Literature Searches we analyzed the growth of one CCP but in reality a researcher would likely go through the process of merging more CCPs into the original network to get a larger list of potential lead compounds However this might yield hundreds or even thousands of potential leads e To assist with logically reducing your lead compound list further there are two tools developed by UNM s Translational Informatics Division that can help refine your results based on promiscuity and reactivity called badapple and smartsfilter respectively These tools can be found in UNM Biocomputing Public Web Applications at pasilla helath unm edu or by going to the CARLSBAD Community link on the CARLSBAD website carlsbad health unm edu and looking under Other Resources gt 48 nttp pasilla heslth unenedu C 3 Googie 2 n n UNM Biocomputing Public Web Applications Computational Tools for Cheminformatics and Biomolecular Discovery m ALLOWED USE These applications are for limited reasonable use by the scientific community and especially academic and non profit researchers worldwide This application server is a standard Linux 4 core 1 processor computer Overuse will interfere with access and performance for others so we ask all fo be considerate In general
52. ndex the document and publication system constraints Priority Patent Information Dec 21 2007 Patent No Kind Date Application No Date pease US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 US 2008 23801P US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 Dec 22 2008 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 ome US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 wo Eds e UIS US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 S US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 ex Pat Appl Publ US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 xum US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 2009 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 CODEN USXXCO US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 Classifications US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 USS14312000 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 Accession Number US 20090163545 Al Jun 25 2009 US 2008 341615 Dec 22 2008 2009 769551 AM1EC1 70220 10 v Note CARLSBAD IDs change so it is recommended in your research to track structures by som
53. ork Targethamesust is drug sles smarts Node Mexht vizmap Caspase 8 20 Node Shape vVizmap Caspase 8 20 Node Width vizmap Caspase 8 20 Unused Properties Edge Color Edge Font Face Edge Font Sae E Edge Label Edge Label Color Edge Label Opactty Edge Label width Edge Une Style Data Panel Edge Line Width E a BY g 8 cony D m4 dot tet C281851 5 Edge Source Arrow Op 124002 4 Edge Source Arrow Sh 132539 6 4 Edge Target arrow Color S105952 16 eie Tevet aon op 243230 Edge Target Arrow Sh C332627 3 oe md C197578 44 Node Border Color pd Em 3 prem CMONT 3 Node Custom Graphics 1 C281839 5 Node Custom Graphics 2 124000 a Node Custom Graphics 3 c281877 5 rode Custom Graphics 4 s1470 35 Loaded 285 compounds 73 scaffolds 14 MCES Q14790 CASP HUMAN 014790 CASP8 HUMAN 10 1 1014790 CASPa_HUMAN 014790 CASP8 HUMAN 14790 CASP8 HUMAN 14790 CASP8 HUMAN 014790 CASP8 HUMAN 014790 CASP8 HUMAN CASP8 HUMAN CASP8 HUMAN Q14790 CASP8 HUMAN _ g Node Attrbute Browser Edge Attrbute Browser Network Attribute Browser etecc2e ct OCC O2 c3nccs3 etecc2cc ecc2ct C s0 NNC s CCICICC C SONCTCC OJO CC C C C O NC CC O O C etccccet C 0 NNC 0 C2C ctecc2c ct ecec2C O NNC CC C C C O NC CC 0
54. orking with despite the date stamp that is automatically applied to the name in SNAKE In addition you must name your file before clicking the search button in order for your filename to appear in the file you download 11 For target queries the expert mode allows you to filter your search by species human mouse and rat are default and target class In the compound query box the expert mode allows for the ability to search compounds and CCPs by CARLSBAD ID This feature can be useful but you should be aware that CARLSBAD IDs are not static and can change so identification by SMARTS or SMILES is recommended snake SubNet Application Kit amp Extractor for CARLSBAD mode normal advanced heip reset target query compound query output view target table show target IDs structure ail araw queny orenter smiles or smarts BC TA name exact sub me exact O subst C simil gt 0 7 enzyme aminoacybdrase prot glutamine glutamyl xfrase s enzyme cytochrome p450 cyp 11 cyp_11acyp_11a1 bd E e enzyme cytochrome p450 cyp_11 cyp_11b cyp fibt scaffold id CARLSBAD ID Subnet tille Caspase 20121212 mces id CARLSBAD ID misc L verbose C Results extracted subnet eG E download subnet for Cytoscape import XGMML 1 1 MB target nodes 1 compound rodes Mp _ BOA woo view subnet with CytoscapeWeb scaffold nodes 442 NOTE CytoscapeWeb r
55. ose values depict a relationship between the target and the compounds the latter of which you are removing with this filter However if you have already applied the filter for activity see the Filtering tools section you will have some idea as to the lowest bioactivity that could be left in your network In addition with the Connect structural patterns to targets tool you have the ability to choose either Scaffolds MCESs or both to connect directly to the target s P cvenape Osi ier See e File de View Select Layout Phagins Help DARRA Momos hs aes B Update Plugins s mn Pongi entail Plugin from File cs Compas S 201212027 Tg network vatapper baaa Vet structure query Advanced Network Merge Carhibad Depict chermistry Network Analysis i Connect structural patterns to targets Sbercase Network Modifications directed sendarty weighted layout peces Li Select structural patterns to keep in ne Structural patterns Ji bcaffoldd J MCES node armenn Browser Edge Attribute Brosser Network Arr te Browser Note To improve the speed of this filter ensure you don t have any nodes selected when applying the filter as Cytoscape will attempt to continuously regenerate structural depictions in the Control Panel If this happens it will not harm anything but it may take a few moments longer to process 26 After following the CARLSBAD Plugin steps described in this
56. ou will then be provided with information on reactivity in the RESULTS at the bottom of the page unmedu smartsfilter elisg Pla B amp mode 9 normal expert help clear input fmt automatic upload Browse or paste smarts select any combo Blake ALARM NMR Glaxo 4 Oprea PAINS run smartsfilter 7 batch fmt smiles sof view depict misc verbose RESULT total 6 passed 6 100 0 failed 0 0 0 failed oprea filters 0 0 0 download smartsfiter out smiles 438 bytes e d pr smartsfilter web app from UNM Biocomputing B ChemAxon JChem from ChemAxon Ltd since Wednesday September 28 2011 times used 565 smarts loaded 79 smarts defines read 235 smartsfilter elapsed time 0m 5s More information on the PAINS and ALARM NMR filters can be found in the following publications Baell J B amp Holloway G A New Substructure Filters for Removal of Pan Assay Interference Compounds PAINS from Screening Libraries and for Their Exclusion in Bioassays Journal of Medicinal Chemistry 53 2719 2740 2010 Huth J R et al ALARM NMR A rapid and robust experimental method to detect reactive false positives in biochemical screens Journal of the American Chemical Society 127 217 224 2005 36 6 Validation As a means of validating CARLSBAD we looked at recent findings linking cyclobenzaprine to serotonin syndrome SS Mestres et al 2011 In t
57. potential lead compounds or repurposed drugs for your target s of interest Auge Le SAQA cm Update Plugins Control Panel Install Plugin from File 5 g Network vattagper CARL Tay Advanced Network Merge Carlsbad gt Depict chemistry Network Analysis Connect structural patterns to targets Subetructure Network Modifications Applyforce directed similarity weighted layout Filtering tools Remove unmergeable CCPs Options Select structural class Remove promiscuous compounds 7 j Nx oo 4 Qu rd OQ 5127255 C320758 3 4 Description Remove unmergeable CCPs X Status Removing unmergeable CCPs SE Rs YA a o Progress em esi 124002 I F NS e Data Panel E Ov SO E E D 54 t _TargetNamestist 5 55 ones smarts 127255 1 3 In eteec2cc eec2ct C O NC3C C390758 5 1014790 CASP8 HUMAN ctcoo cct CN2c3eccd ce3C s C281851 5 014790 CASP8 HUMAN Cc C CC C s0 NC1CC sO C124002 4 Q14790 CASP8 HUMAN CC CKXC cONC CCCOO 5132529 1 3 o l 1ecc2cc ece2e1 C O NNC n x S167119 1 5 o cteec ect CN2e3ece ec3C e 132521 TAE 13 10 ji c1coc2ceicec2c1 CONNC 5132539 6 4 in eteec ect C O NNC 0 C2 o s80293 1 4 Iu cteee ect CSCC 0 CNC 0 y C2M871 5 I014790 CASP8 HUMAN CcciceecoNNctCC eo Song n S105852 16 6 0 ctecc2c c1 OCC O2 c3ncecs3 H Ct4104 5
58. r import by Cytoscape or 2 viewing and analyzing via Cytoscape Web Sub Network Any subset of a larger network Target A biological target most likely associated with some pathology such as a protein involved in the apoptotic pathway Target of Interest TOI The target that is the focus of a network analysis val std A bioactivity that has been log molar transformed so that a val std activity 5 0 is the same as a an IC50 or EC50 value gt 10 uM 43 10 11 12 13 14 CARLSBAD References Bolton E E et al 2008 PubChem Integrated Platform of Small Molecules and Biological Activities Annual Reports in Computational Chemistry 4 217 241 CHORD version 1 3 gNova Inc San Diego CA USA www gnova com 2009 Gaulton A et al 2012 ChEMBL a large scale bioactivity database for drug discovery Nucleic Acids Research 40 D1100 D1107 laccard P 1901 tiide camnarative de la distrihutian florale dans ine portion des Alpes et des Jura Bulletin de la Soci t Vaudoise des Sciences Naturelles 37 547 579 JChem Base version 5 7 was used for cheminformatics processing JChem 5 5 2011 ChemAxon http www chemaxon com Lopes C T et al 2010 Cytoscape Web an interactive web based network browser Bioinformatics 26 2347 2348 OEChem version 1 7 4 OpenEye Scientific Software Inc Santa Fe NM USA www eyesopen com 2010 Olah M et al 2008 WOMBAT and W
59. rchers with a well defined question towards a hypothesis but CARLSBAD can only go so far This section focuses on some steps researchers can take to help transition from their CARLSBAD findings to experimentation e Literature Searches After conducting a process of discovering potential new chemical and biological relationships the researcher is left with the task of confirming that those relationships haven t been previously studied and then clearly defining their own individual hypothesis for testing CARLSBAD cannot define your hypothesis however some steps you might want to consider include Searching a database like SciFinder to see if a possible lead that you identified with CARLSBAD has any literature relating your target and the potential lead compound Searching a database like Web of Science to see what relationships may exist between the class of molecule and target for which you are interested As was highlighted in the previous section Merging CARLSBAD Networks the merging of networks generated three new compounds for one of the 70 CCPs that we refined the network down to and explored We are going to concentrate here on the compound with the CARLSBAD ID C790457 and SMILES CCOc1cccc c1 c2csc n2 C3COc4ccccc403 merge compound Z edges smiles CCOc1cccc c1 c2csc n2 C3COc4ccccc403 O layout ForceDirected E PubChem SID 17512831 v Te deg tgt2 j tgt labels default Lel id C790457 E cpd labels
60. rk under the conditions stated herein The Document below refers to any such manual or work Any member of the public is a licensee and is addressed as you You accept the license if you copy modify or distribute the work in a way requiring permission under copyright law A Modified Version of the Document means any work containing the Document or a portion of it either copied verbatim or with modifications and or translated into another language A Secondary Section is a named appendix or a front matter section of the Document that deals exclusively with the relationship of the publishers or authors of the Document to the Document s overall subject or to related matters and contains nothing that could fall directly within that overall subject Thus if the Document is in part a textbook of mathematics a Secondary Section may not explain any mathematics The relationship could be a matter of historical connection with the subject or with related matters or of legal commercial philosophical ethical or political position regarding them The Invariant Sections are certain Secondary Sections whose titles are designated as being those of Invariant Sections in the notice that says that the Document is released under this License If a section does not fit the above definition of Secondary then it is not allowed to be designated as Invariant The Document may contain zero Invariant Sections If the Document does not identify any Invariant
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63. sphelides with a thiazole side chain Author s Ahmed Kanwal Matsuya Yuji Nemoto Hideo et al Source CHEMICO BIOLOGICAL INTERACTIONS Volume 177 Issue 3 Pages 218 226 DOI 10 1016 cbi 2008 10 030 Published FEB 12 2009 Times Cited 8 from Web of Science UNMFall Text View abstract R Tite Synthesis formulation and in vitro evaluation of a novel microtubule destabilizer SMART 100 Author s Li Feng Lu Yan Li Wei et al Source JOURNAL OF CONTROLLED RELEASE Volume 143 Issue 1 Pages 151 158 DOI 10 1016fjconrel 2009 12 028 Published APR 2 2010 Times Cited 4 from Web of Science UN Mru Text View abstract E19 Tite Synthesis of Imidazothiazole Chalcone Derivatives as Anticancer and Apoptosis Inducing Agents Author s Kamal Ahmed Dastagiri D Ramaiah M Janaki et al Source CHEMMEDCHEM Volume 5 Issue 11 Special issue SI Pages 1937 1947 DOI 10 1002 cmdc 201000346 Published NOV 8 2010 Times Cited 4 from Web of Science LIN MFoll Text View abstract iwebofknowledge com full_record do product WOS amp search modezGe Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem an in vitro analysis Thus we might hypothesize that 2 2 3 dihydro 1 4 benzodioxin 2 yl 4 3 ethoxyphenyl thiazole is a potential lead compound for Caspase 8 Tip You can use the attribute is_ drug to determine if a compound is a known drug thus turning your lead co
64. t can be found at the end of the manual and each item that is defined appears in red font the first time it is mentioned in the manual content CARLSBAD is a database and knowledge inference system that integrates multiple bioactivity datasets in order to provide researchers with novel capabilities for the mining and exploration of available structure activity relationships SAR throughout chemical biology space The powerful cheminformatics and pattern recognition algorithms combined with network analysis methodology allow researchers using CARLSBAD to generate hypotheses involving the relationships between biological targets chemical compounds and their common chemical patterns CCPs The CARLBAD platform consists of a web based extraction tool called SNAKE and a network analysis plugin for Cytoscape called CARLSBAD In addition the use of Cytoscape enables researchers to infer novel associations via the powerful biological network visualization environment that Cytoscape provides i Gytoxcope Desktop New Session lt O ia File Edt View Select Layout Plugins Help S n a aa alla 9 5 Pr D ee ii Control Panel C Romig elec ecl C CIC OINC 0 52 20120200 Tere x Jg Network vatiagper CARLSBAD Editor Filters rout etuctre query Suetructure Seach Options 2 Q Y v e JO A p c579246 3 o s D A Data Panel AAD homi Boke y m mies smarts 13397 T3392 T3391 ER dde 13389 20694 ci60016 in T a T3372 O 1
65. t structure query nd Substructure Search Options 790457 392341 Data Panel fa BOKE Ej fg D valstd dass confidence C790457 pp T3657 54 activity 7 790457 pp T3764 54 activity 7 o IO 392341 pp 558036 cpd2scaf i C392341 pp T942 58 adwy 7 N EX C315405 pp T149 537 activity 7 C790457 pp 558036 cpd2scaf 858036 pc 1712 C315405 pp 558036 epd2scaf sseose csis os TEENE cape ntrtute roves RESORT ome Leaded 3 compounds ET saos TS MCES In addition by viewing the Data Panel towards the bottom of the screen with the Edge Attribute Browser tab selected we can see that there are four new activities and they are above 5 0 log molar remember we lost the activity value between the original scaffolds and Caspase 8 in a previous step when we connected the CCPs to the target by removing the compounds known to associate with Caspase 8 from the CARLSBAD database but we know that activity is also above 5 0 log molar since we filtered out all compounds with activities below 5 0 Also Note When growing a network if a node is a CCP or a compound be sure to use the appropriate query area in SNAKE In addition be aware that you can use node attribute information from your current network to facilitate your search in SNAKE i e SMILES or CARLSBAD ID however if usin
66. the compound query options in the center box To perform a substructure or common chemical pattern CCP query you can either draw the structure with the button in the compound query box or enter the SMILES SMARTS in the space below the draw query button The final box misc allows you to name the network file that you will download from SNAKE and open in Cytoscape for analysis with the CARLSBAD plugin described further in the CARLSBAD Plugin to Cytoscape section of this manual snake SubNet Application Kit amp Extractor for CARLSBAD mode normal advanced help reset target query compound query misc name casp exact sub name 9 exact sub subnel_fitles CARLSBAD SubNet 20121212 descr exact sub substructure draw query id type any browse targets J verbose or enter smiles or smarts Results ERROR extract2XGMML failed no targets found since Monday January 9 2012 times used 461 snake elapsed time Om 1s Note There is a glossary at the end of this manual with many definitions for items mentioned in the manual and these defined items appear in red font the first time they are mentioned in the manual content i e the common chemical patterns CCP example found above Query Options In the target query box you can search by the target name name a description of the target descr or one of the 19 identifiers id whic
67. tions Filtering tools i Remove unmergeable CCPs ii Remove promiscuous compounds iii Remove specified activity edges Using the CARLSBAD plugin options Additional tools i Apply force directed similarity weighted layout ii Select structural class iii Connect structural patterns to targets 4 Merging CARLSBAD Networks 28 5 Next Steps 31 Literature Searches Additional Biocomputing Tools for Filtering i BadApple ii SmartsFilter 6 Validation 37 7 Appendix 38 Applying Different Visual Styles to a CARLSBAD Network 8 Glossary 41 9 CARLSBAD References 44 10 GNU Free Documentation License 45 1 Installation and Downloading Procedures To begin using the CARLSBAD platform you will need to obtain a CARLSBAD group license free for academic and non commercial usage install Cytoscape free a ChemAxon license free for some categories such as academics and non commercial usage and load the CARLSBAD plugin to Cytoscape This section will focus on how to download and install these applications e Obtaining a CARLSBAD User Group License In order to begin using the subnet extractor tool SNAKE see section 2 of this manual please visit carlsbad health unm edu cgi bin cb_user_app cgi to apply for a license which can take several days to approve e Installing Cytoscape Cytoscape is an open source bioinformatics software platform that CARLSBAD is able to utilize via the plugin for powerful network visualization
68. ucture a Show CARLSBAD info Substrate s Search R 4 d S j S70080 Options E Visual Mapping Bypass gt L s Structure node setibut _ gt Depict chemical structure Show CARLSBAD info lo ET KAY PARA HIE Data Panel ZEBE deg pd deg tot smes smarts nare Targetiamesust UnProt D 1 8 BEG n 70080 370080 Node Attribute Bronger Edge Attribute Browser Network Attribute Browser Loaded 411 compounds 458 scaficies 70 MCES Note This section is designed to help you get comfortable navigating the CARLSBAD plugin to Cytoscape In this section you will find where and what attributes are included in the CARLSBAD platform i e bioactivities common identifiers SMILES structures etc However a more detailed explanation of individual attributes can be found in the Glossary at the end of this manual 18 you can obtain all the attribute information for all nodes or a subset of nodes in the Data Panel by selecting the Grid button in the top left of the Data Panel and then checking the attributes you wish to display depicted below Also you can simply check the 2X Box and 2X Check Mark button to the right of the Grid button which will display all the attribute information in the Data Panel Dc LL RN File Edit View Select Layout Plugins Help S naaa alda ane LB Control Panel E FL Caspase 8 201202 Tg Network Vattagper CARLSB
69. uery box there is a link towards the bottom that can take you to a searchable html listing of all the targets contained in CARLSBAD e Result Options If you scroll down to the Results section you will find some basic attributes in the extracted subnet section information on the targets in the targets section and three buttons The button at the bottom of the page download targets downloads a csv file which can be opened with a program like Excel by Microsoft that contains the target information depicted in this screenshot as well as additional identifier information The button at the top download subnet for Cytoscape import allows you to download a SNAKE file that can be opened in Cytoscape for visualization and analysis with the CARLSBAD plugin described further in the CARLSBAD Plugin to Cytoscape section of this manual Finally the button titled view subnet with CytoscapeWeb allows you to quickly visualize your network without having to import it into Cytoscape Results extracted subnet l Qr Axe Web view subnet with CytoscapeWeb Scaffold nodes 2139 NOTE CytoscapeWeb requires Flash plugin Since total nodes gt 1000 Cytoscape Web not recommended target nodes 15 compound nodes 2361 mces nodes 579 total nodes 5094 activity edges 4083 scaffold edges 4066 mces edges 1368
70. ute Browser Edge Attribute Browser Network Attribute Browser Note More discussion of how to use these tools and what they do can be found in the Using the CARLSBAD plugin options section of this manual 13 In addition CARLSBADs import tools can be found in the File Import menu at the top of the Cytoscape window as depicted here 19 cose Deskop New Sexo aa A c w ee eee File Edit View Select Layout Plugins Help New p f 23 y C gs mo JI dcs Save CtrleS E Save as Ctrisshirtes f ARSEAP Import gt Network Multiple File Types Export 4 Network from Table Text MS Excel Recently Opened 1 Network from Web Services Print t Node Attributes Quit Cti Q Attribute from Table Text MS Excel Edge Attributes Ontology and Annotation Attribute Expression Matrix Ctrl E Vizmap Property File Import attributes from Biomart Import Attributes from NCBI Entrez Gene Load CARLSBAD network from SNAKE Merge CARLSBAD networks Data Panel aOR 3 6N D _deg_cod deg tot TargetNamestist is drug smies smarts Node Attribute Browser Edge Attribute Browser Network Attribute Browser As you can see the first of the two import tool options is Load CARLSBAD network from SNAKE After selecting this option Note More discussion of how to use the second option in this menu Merge CARLSBAD networks
71. xplicit permission from the previous publisher that added the old one The author s and publisher s of the Document do not by this License give permission to use their names for publicity for or to assert or imply endorsement of any Modified Version 5 COMBINING DOCUMENTS You may combine the Document with other documents released under this License under the terms defined in section 4 above for modified versions provided that you include in the combination all of the Invariant Sections of all of the original documents unmodified and list them all as Invariant Sections of your combined work in its license notice and that you preserve all their Warranty Disclaimers The combined work need only contain one copy of this License and multiple identical Invariant Sections may be replaced with a single copy If there are multiple Invariant Sections with the same name but different contents make the title of each such section unique by adding at the end of it in parentheses the name of the original author or publisher of that section if known or else a unique number Make the same adjustment to the section titles in the list of Invariant Sections in the license notice of the combined work In the combination you must combine any sections Entitled History in the various original documents forming one section Entitled History likewise combine any sections Entitled Acknowledgements and any sections Entitled Dedications You must delete all
72. y BDEBSE EH a tn amp ano dit a V eos RET tagetanesat wes E Le it rere J 5 A a 1014700 CASP ciaoe OCICSGH OCIS PO XO Soc C156 i 1014790 Cases PROGO 00C 10 C J014790 cAsPa PECGHIICCI20 0C10 1 C269454 ni ji 014790 CASPE cQ cci zOpc1O 209456 1014790 CASP8 CC CyC 0 CC 0 0 ci O cF SO 196336 i OzCctesan te 16Oc2ececc201 M37352 e mmnm 8 ia pejoce scons 20 O c 10cc2NC u16028 J014799 CASPA_ CCCICIPONCGIGHICCI O OCIPOICCCG e cuz 87 38 Cloceice Oeaeceee 5924 Cy x 1014790 CASPR caase ores A n 014790 CASP8 ctccc2ecrcocact C232516 d 1014790 CASPA 328024 p t 034790 CASP C269493 B 1014790 Cases C370697 37352 neoze Node armena Browser a Note To improve the speed of this filter ensure you don t have any nodes selected when applying the filter as Cytoscape will attempt to continuously regenerate structural depictions in the Control Panel If this happens it will not harm anything but it may take a few moments longer to process 23 e Using the CARLSBAD plugin options Additional tools In the CARLSBAD plugin you will find some additional tools that CARLSBAD offers to assist with your analysis in addition to the Filtering Tools discussed in the previous section Apply force directed similarity weighted layout The CARLSBAD plugin provides the ability to weigh the network visualization based on node and edge similarities such as chemic

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