Bridging Bioinformatics and Chem(o)informatics Gary Wiggins School of Informatics Indiana University wiggins@indiana.edu Yan He (SLIS MLS Student) Meredith Saba (SLIS MLS Student)

Provocative Thought “While much bioscience is published with the knowledge that machines will be expected to understand at least part of it, almost all chemistry is published purely for humans to read.” Murray-Rust et al. Org. Biomol. Chem. 2004, 2, 3201.

Overview of the Talk Review of ACS CINF 2004 Papers Review of Relevant Articles Public Chemistry Databases and Data Repositories with Bioinformatics Info/Links Overview of Web Services NIH-funded Projects Underway or Planned at Indiana University

“The Bigger Picture — Linking Bioinformatics to Cheminformatics” American Chemical Society Division of Chemical Information (CINF) Symposium, Anaheim, Spring 2004 All-day session with 16 papers http://www.acscinf.org/new/docs/meetings/227nm/227cinfabstracts.htm

Problems from ACS CINF 2004 Both technical and people factors hinder knowledge exchange between biology and chemistry. (Lipinski) People Problems per Chris Lipinski Meta data capture is complicated by people issues, particularly those between chemists and biologists. Discipline-based disconnects occur distressingly often and are frequently overlooked as a cause of lost productivity.

Interdisciplinary Collaborations: Biology and Chemistry [What’s] “... important for these collaborations is, not only do you have to accept the other guy’s paradigm or at least live with it; you have to be willing to accept the other guy’s foibles or your perception of the other guy’s foibles (and recognize the opposite of this). We each have our own approaches to how we do science, and it’s just different cultures.” --Thom Kauffman interview in ACS LiveWire, March 2005, 7.3. http://pubs.acs.org/4librarians/livewire/2006/7.3/profile.html

Some Questions from the ACS CINF 2004 Symposium "Find all proteins related to protein A (i.e. within a given path length of A) in a protein interaction graph, and retrieve related assay results and compound structures.” “Find all pathways where compound X inhibits or slows a reaction, and retrieve Gene Ontology classifications for all proteins involved in the reaction.”

Problems from ACS CINF 2004 Commercial vs. public data Batch mode data processing possible in biology, but primitive in chemistry Primary HTS data has a very high noise factor Data format standardization problem Chemoinformatics and bioinformatics use completely different data formats and analysis tools Chemical and protein sequence information has been largely analyzed separately

Solutions from ACS CINF 2004 Linking biological and chemical information in computational approaches to predict biological activity, ADME profiles, and adverse drug reactions (ADR) Energetics of binding for more accurate and sensitive chemical representation of DNA-protein interactions A discovery informatics platform that facilitates archival, sharing, integration, and exploration of synthetic methods and biological activity data

Solutions from ACS CINF 2004 Data pipelining approach makes it possible to apply bioinformatics and chemoinformatics data and analyses together. Visualizations are the best way for people to understand data.

Solutions from ACS CINF 2004 Cabinet (Chemical And Biological Information NETwork, formerly Fedora) servers include Metabolic pathway network chart (Empath) Protein-Ligand Association Network (Planet) Enzyme Commission Codebook (EC Book) Traditional Chinese Medicines (TCM) World Drug Index (WDI), and others. Built on the Daylight HTTP toolkit http://www.metaphorics.com/products/cabinet.html

Overview of the Talk Review of Relevant Articles Review of ACS CINF 2004 Papers Review of Relevant Articles Public Chemistry Databases and Data Repositories with Bioinformatics Info/Links Overview of Web Services NIH-funded Projects Underway or Planned at Indiana University

What is Chemoinformatics? (Brown) “…the essence of chemoinformatics is integration and focus rather than its components, which are independent disciplines.” Supporting disciplines: Chemical information Computational chemistry Chemometrics

Chemoinformatics and Disease

Toolkits as Integrators (Brown) Companies such as Daylight, Advanced Visual Systems, OpenEye, and SciTegic provide integration systems for: Statistical methods Text mining Computational chemistry Visualization

Genego’s MetaDrug Product Toxicogenomics platform for the prediction of human drug metabolism and toxicity of novel compounds Enables the visualization of pre-clinical and clinical high-throughput data in the context of the complete biological system Integrates chemical, biological, and protein function data http://www.genego.com/

BioWisdom Examination of vast amounts of available information using its Sofia KnowledgeScan methodology SRS data integration platform http://www.biowisdom.com/

Lessons from Hip Hop (Salamone) Mashup technique Bring together disparate informatics, biological, chemical, and imaging information when conducting research Example of an integration tool: iSpecies.org A search for a species returns a page with NCBI genomics information, Yahoo images of the species, and articles culled from Google Scholar

iSpecies.org Search For mus musculus

Chemogenomics and Chemoproteomics (Gagna) Chemogenomics (def.)—The description of all potential drugs that can be used against all possible target sites, OR the actions of target-specific chemical ligands and how they are used to globally examine genes Chemoproteomics (def.)—Uses chemistry to characterize protein structure and functions They are “. . . a form of chemical biology brought up to date in the area of genome and proteome analysis.”

New Interdisciplinary Journals ACS Chemical Biology (ACS) ChemBioChem; A European Journal of Chemical Biology (Wiley/VCH) Chemical Biology and Drug Design (Blackwell) JBIC; Journal of Biological and Inorganic Chemistry (Springer) Journal of Biochemical and Molecular Toxicology (Wiley) Molecular Biosystems (RSC) Nature Chemical Biology (Nature Publishing) Organic & Biomolecular Chemistry (RSC)

Open Source Software (Geldenhuys) Log P calculator from Interactive Analysis http://www.logp.com University of Utah’s Computational Science and Engineering Online Can submit jobs for molecular mechanics, quantum chemical calculations, and biomolecular interfaces for viewing PDB files http://www.cse-online.net Virtual Computational Chemistry Laboratory http://www.vcclab.org

The Blue Obelisk (Guha) Several open chemistry and chemoinformatics projects that have pooled forces to enhance interoperability Maintain: Chemoinformatics Algorithms Dictionary Data Repository for standardized data for chemical properties and other facts (e.g., mass) http://www.blueobelisk.org/

BlueObelisk.org Working collaboratively on projects such as: Chemistry Development Kit (CDK) JChemPaint Jmol JUMBO NMRShiftDB Octet Open Babel QSAR World Wide Molecular Matrix (WWMM)

Barriers to the Use of Open Source Software Unix command line Problem: Lack of known standards and datasets of compounds for validation, e.g., in docking programs

Lessons from the Human Genome Project (Austin) Keys to success in the HGP were: Comprehensiveness Commitment to open access to the sequence as a research tool without encumbrance Proposed tools for a “genome functionation toolbox”: Whole-genome transcriptome and proteome characterization Development of small inhibitory RNAs (siRNAs) and knockout mice for every gene Small molecules and the druggable genome

ChemDB http://cdb.ics.uci.edu/CHEM/Web/

ChEBI, Chemical Entities of Biological Interest Dictionary of molecular entities focused on small chemical compounds Features an ontological classification, showing the relationships between molecular entities or classes of entities and their parents and/or children

Vioxx Entry in ChEBI

The IUPAC International Chemical Identifier (InChI) Open source, non-proprietary, public-domain identifier for chemicals String of characters that uniquely represent a molecular substance Independent of the way the chemical structure is drawn Enables reliable structure recognition and easy linking of diverse data compilations Accepts as input MOLfiles (or SDfiles) and CML files Download the program to your computer at: http://www.iupac.org/inchi/license.html

Generation of InChI for Vioxx with wInChI

Vioxx Entry in PubChem Compounds Found with InChI

Vioxx Bioassay Data in PubChem

Vioxx PubChem Link to External Sources of Information

The Elsevier MDL/NIH Link via PubChem and DiscoveryGate Cross-indexes PubChem to the Compound Index hosted on Elsevier MDL’s DiscoveryGate platform MDL added 5 million structures from PubChem to their index, resulting in over 14 million unique chemical structures Links go both ways Can move from biological data in PubChem to bioactivity, chemical sourcing, synthetic methodology, and EHS data in DiscoveryGate sources

Elsevier MDL’s xPharm Comprehensive set of records linking: Agents (compounds) (2300) Targets (600) Disorders (450) Principles that govern their interactions (180) Answers questions such as: What targets are associated with control of blood pressure? What adverse effects are associated with monoamine oxidase inhibitors?

Text Datamining (Banville) “In the pharmaceutical field, it is ideally the marriage of biological and chemical information that needs to be the ultimate focus of text data mining applications.” Problems: Lack of universal publication standards for identifying each unique chemical entity Selective indexing policies of A&I services Need to understand how chemical structures link to biological processes

Chemical Datamining Software SureChem http://surechem.reeltwo.com/ CLiDE Recognizes structures, reactions, and text http://www.simbiosys.ca/clide/ OSCAR “OSCAR1” to check experimental data http://www.ch.cam.ac.uk/magnus/checker.html http://www.rsc.org/Publishing/ReSourCe/AuthorGuidelines/AuthoringTools/ExperimentalDataChecker/ CSR (Chemical Structure Reconstruction) http://www.scai.fraunhofer.de/uploads/media/MZ-ERCIM05_04.pdf MDL DocSearch—combines MDL’s Isentris platform and EMC’s Documentum

Overview of the Talk Review of ACS CINF 2004 Papers Review of Relevant Articles Public Chemistry Databases and Data Repositories with Bioinformatics Info/Links Overview of Web Services NIH-funded Projects Underway or Planned at Indiana University

Themes from SwissProt’s 20th Anniversary Conference, “In silico Analysis of Proteins” Knowledgebases, databases and other information resources for proteins Sequence searches and alignments Protein sequence analysis Protein structure prediction, analysis and visualization Proteomics data analysis

Chemoinformatics Databases (Jónsdóttir) Lists databases relevant to drug discovery and development, including: General databases DBs for screening compounds DBs for medicinal agents DBs with ADMET properties DBs with physico-chemical properties Curiously does not mention Chemical Abstracts

Databases with Protein and Ligand Information (Jónsdóttir) Protein Data Bank Target Registration Database Relibase—uses structural info to analyze protein-ligand interactions; Relibase+ for protein-protein interaction searching Cambridge Structural Database KEGG LIGAND DB for enzyme reactions http://www.genome.ad.jp/ligand

Other Databases with Protein and Ligand Information SitesBase--a database of known ligand binding sites within the PDB http://www.bioinformatics.leeds.ac.uk/sb/main.html Binding MOAD http://www.bindingmoad.org/ sc-PDB (Kellenberger) http://bioinfo-pharma.u-strasbg.fr:8080/scPDB/index.jsp

sc-PDB http://bioinfo-pharma.u-strasbg.fr:8080/scPDB/index.jsp

Isatin Search on sc-PDB

Other Databases with Protein-Protein Interaction Data (Jónsdóttir) YPD, Yeast Proteome Database (for proteins from S. cerevisiae) http://www.biobase.de/pages/index.php?id=139 Human Protein Reference Database http://www.hprd.org/ BIND, Biomolecular Interaction Network Database (ceased as of 11/16/2005?) http://www.bind.ca/Action

International Molecular Exchange (IMEx) Consortium http://imex BIND (http://www.blueprint.org) The Blueprint Initiative AsiaPte. Ltd, Singapore and The Blueprint Initiative North America,Toronto Canada DIP (http://dip.doe-mbi.ucla.edu) UCLA-DOE Institute for Genomics & Proteomics IntAct (http://www.ebi.ac.uk/intact), EMBL–European Bioinformatics Institute, Hinxton, UK; MINT (http://mint.bio.uniroma2.it/mint/) University of Rome “Tor Vergata”, Rome Italy MPact (http://mips.gsf.de/genre/proj/mpact), MIPS / Institute for Bioinformatics, Munich, Germany.

Protein Sites from IU I533 Students and others LigandDepot—integrated source for small molecules http://ligand-depot.rutgers.edu/index.html PSIPRED Protein Structure Prediction Server http://bioinf.cs.ucl.ac.uk/psipred/ DSSP--a database of secondary structure assignments (and much more) for all protein entries in the PDB http://swift.cmbi.ru.nl/gv/dssp/ Dr. Predrag Radivojac’s I690 class on Structural Bioinformatics http://www.informatics.indiana.edu/predrag/2006springi690/2006springi690.htm

Protein Secondary Structure Prediction Methods Neural Network Rule Based Other Machine Learning Homology Based

Protein Secondary Structure Prediction Software PredictProtein http://www.predictprotein.org/ Chou-Fasman http://fasta.bioch.virginia.edu/fasta_www/chofas.htm NN Predict http://www.cmpharm.ucsf.edu/~nomi/nnpredict.html

Structure-Based Docking Methods Scans many small molecules and “docks” them to a site of interest on a protein structure Predicts free energy of binding Filters thousands of compounds relatively quickly Top hits can be used for more rigorous computational/experimental characterization and optimization

Structure-Based Docking Methods http://dock.compbio.ucsf.edu/ Accelrys’s Insight (built on DOCK) http://www.accelrys.com/products/insight/ FlexX http://www.biosolveit.de/FlexX/ Glide http://www.schrodinger.com/ProductDescription.php?mID=6&sID=6 GOLD http://www.ccdc.cam.ac.uk/products/life_sciences/gold/

Useful Structure Databases ModBase http://modbase.compbio.ucsf.edu/modbase-cgi-new/search_form.cgi Dali Database (Fold classification; based on PDB) http://ekhidna.biocenter.helsinki.fi/dali/start Protein Structure Analysis, Comparison, &/or Classification [Guide] http://www.bio.vu.nl/nvtb/Structures.html

SCOP, Structural Classification of Proteins Curated database of structural and evolutionary relationships All known protein folds (v. 1.69, July 2005) 70,859 domains organized into 2,845 families, 1,539 superfamilies, and 945 folds Detailed information about close relatives Links to coordinates, images of structures, interactive viewers, and literature references http://scop.mrc-lmb.cam.ac.uk/scop/

SCOP Search Options Homology search yields a list of structures with significant levels of sequence similarity Keyword search matches words in SCOP and PDB

CATH Protein Structure Classification Like SCOP, structured hierarchically by: Class (determined by secondary structure) Architecture (overall shape, e.g., barrel, sandwich, roll, etc.) – no equivalent in SCOP Topology (grouped into fold families based on overall shape and connectivity of secondary structures) Homologous Superfamily (domains thought to share a common ancestor) As of January 2005, had 43,229 domains classified into 1,467 superfamilies and 5,107 sequence families; A protein family database (CATH-PFDB) contained a total of 616,470 domain sequences classified into 23,876 sequence families http://cathwww.biochem.ucl.ac.uk/latest/index.html

CATH Search Options Can browse or search the classification by CATH code CATH codes can be used to search other databases, e.g., DHS, Gene3D, and Impala

Gasteiger’s Biochemical Pathways Database Database of biochemical pathways that represents chemical structures and reactions on the atomic level Gives access to each atom and bond of the substrates of enzyme reactions Allows the study of transition state hypotheses of enzyme reactions Analysis of the physicochemical effects operating at the reaction site allows a classification of enzyme reactions that goes beyond the traditional EC code for enzymes. 1533 biochemical molecules and 2175 reactions http://www2.chemie.uni-erlangen.de/services/biopath/index.html

A Gene Expression Database for NCI60 (Scherf) Published in Nature Genetics, 2000 First study to integrate gene expression with molecular pharmacology databases Gene expression profiles for NCI60 assessed using microarray technology Gene-drug relationships investigated by how the gene transcription levels vary with respect to drug activities

Correlation Matrix Between Drug Activity and Gene Expression

Other Relevant Databases/Servers Each year Nucleic Acids Research publishes a Database Issue in January and a Web Server Issue in July (See refs in Bibliography section). Examples from the most recent issues: Databases Servers KEGG BASys PDB BRIDGEP PINT SCRATCH MutDB Glyprot GLIDA I2I-SiteEng DrugBank PatchDock SPACE SymmDock DeNovoID

Overview of the Talk Overview of Web Services Review of ACS CINF 2004 Papers Review of Relevant Articles Public Chemistry Databases and Data Repositories with Bioinformatics Info/Links Overview of Web Services NIH-funded Projects Underway or Planned at Indiana University

Web Services Overview What are “Web Services”? A distributed invocation system built on Grid computing Independent of platform and programming language Built on existing Web standards A service oriented architecture with Interfaces based on Internet protocols Messages in XML (except for binary data attachments)

Service-Oriented Architecture From Curcin et al. DDT, 2005, 10(12),867

Web Services for Chemistry: Problems Performance and scalability Proprietary data Competition from high-performance desktop applications -- Geoff Hutchison, it’s a puzzle blog, 2005-01-05 ALSO: Lack of a substantial body of trustworthy Open Access databases Non-standard chemical data formats (over 40 in regular use and requiring normalization to one another)

Overview of the Talk Review of ACS CINF 2004 Papers Review of Relevant Articles Public Chemistry Databases and Data Repositories with Bioinformatics Info/Links Overview of Web Services NIH-funded Projects Underway or Planned at Indiana University

Indiana University Planned Projects: http://www.chembiogrid.org Design of a Grid-based distributed data architecture Development of tools for HTS data analysis and virtual screening Database for quantum mechanical simulation data Chemical prototype projects Novel routes to enzymatic reaction mechanisms Mechanism-based drug design Data-inquiry-based development of new methods in natural product synthesis

Web Services for Chemistry at IU Purpose Technologies Interaction Layer Interactive software for creative access and exploitation of information by humans Microsoft .NET Smart Clients, portlets, Java applets, email and browser clients, visualization technologies Aggregation Layer Workflows and data schemas customized for particular domains, applications and users BPEL, Taverna and other workflow modeling tools, aggregate web services Web service layer Comprehensive data and computation provision including storage, calculation, semantics and meta-data exposed as web services Apache web services, SOAP wrappers, WSDL, UDDI, XML, Microsoft .NET

NCI Developmental Therapeutics Program (DTP) Downloadable data: In vitro 60 cell line results in vitro anti-HIV results Yeast assay 200,000+ chemical structures molecular targets microarray data Or search the database at: http://dtp.nci.nih.gov/docs/dtp_search.html

IU Database of NIH DTP Data Contains over 200,000 chemical structures tested in 60 cellular assays from different human tumor cell lines Also includes microarray assay profiles for the untreated cell lines (~14,000 datapoints) A local PostgreSQL database containing the data that is exposed as a web service Using workflows and complex SQL queries, we can do advanced data mining that exploits the chemical, biological and genomic information for particular audiences (chemists, biologists, etc)

Mining the NIH DTP database ~14,000 gene expression values 60 cell lines Cell lines can be clustered based on gene expression similarity ~200,000 compounds Compounds can be clustered based on similarity of profile across cell lines, or by chemical structure fingerprint similarity

Use of Taverna at IU A protein implicated in tumor growth is supplied to the docking program (in this case HSP90 taken from the PDB 1Y4 complex) The workflow employs our local NIH DTP database service to search 200,000 compounds tested in human tumor cellular assays for similar structures to the ligand. Client portlets are used to browse these structures Once docking is complete, the user visualizes the high-scoring docked structures in a portlet using the JMOL applet. Similar structures are filtered for drugability, and are automatically passed to the OpenEye FRED docking program for docking into the target protein. A 2D structure is supplied for input into the similarity search (in this case, the extracted bound ligand from the PDB IY4 complex) Correlation of docking results and “biological fingerprints” across the human tumor cell lines can help identify potential mechanisms of action of DTP compounds

Taverna Workflow Workflow definition Available web services (WSDL) Visual depiction of workflow

Taverna in Action

Overall Workflow

Pre-Closing Quote “There is not going to be a ‘voila’ moment at the computer terminal. Instead, there is systematic use of wide-ranging computational tools to facilitate and enhance the drug discovery process.” Jorgensen. Science, March 19, 2004, 303, 1814.

Closing quote “The future of chemistry depends on the automated analysis of chemical knowledge, combining disparate data sources in a single resource, such as the World-Wide Molecular Matrix, which can be analysed using computational techniques to assess and build on these data.” Townsend et al. Org. Biomol. Chem. 2004, 2, 3299.

Post-closing quote: zzzzzCAS “In an industry first, Chemical Abstracts Service (CAS) has unveiled a revolutionary new literature searching tool which will permit scientists to search and retrieve the world’s chemical literature—including patents and obscure technical reports—in their sleep.” --Author unknown

Acknowledgements Randy Arnold Xiao Dong Sean Mooney Peter Murray-Rust David J. Wild I533 Chemical Informatics Seminar Students Elsevier Science

Bibliography: Articles, Books, and Conference Papers “The Bigger Picture: Linking Bioinformatics to Cheminformatics” [CINF Symposium] Abstracts [1-16], 227th ACS National Meeting Anaheim, CA, March 28-April 1, 2004 http://www.acscinf.org/new/docs/meetings/227nm/227cinfabstracts.htm Austin, C.P. “The completed human genome: implications for chemical biology.” Current Opinion in Chemical Biology 2003, 7, 511-515. Bajorath, Jürgen, ed. Chemoinformatics: concepts, methods, and tools for drug discovery. Totowa, N.J. : Humana Press, c2004. (Methods in molecular biology ; v. 275) Banville, Debra L. “Mining chemical structural informationo from the drug literature.” Drug Discovery Today January 2006, 11(1/2), 35-42. Brown F. “Editorial opinion: chemoinformatics - a ten year update.” Current Opinion in Drug Discovery and Development 2005 May; 8(3): 298-302.

Bibliography: Articles (cont’d) Coles, Simon J.; Day, Nick E.; Murray-Rust, Peter; Rzepa, Henry S.; Zhang, Yong. “Enhancement of the chemical semantic web through InChIfication.” Organic & Biomolecular Chemistry 2005, 3, 1832-1834. Curcin, Vera; Ghanem, Moustafa; Guo, Yike. "Web services in the life sciences." Drug Discovery Today 2005, 10(12), 865-871. Gagna CE, Winokur D, Clark Lambert W. “Cell biology, chemogenomics and chemoproteomics.” Cell Biol Int. 2004; 28(11): 755-64. Geldenhuys, W.J.; Gaasch, K.E.; Watson, M.; Allen, D.D.;Van Der Schyf, C.J. “Optimizing the use of open-source software applications in drug discovery.” Drug Discovery Today February 2006, 11(3/4), 127-132. Guha, R.; Howard, M.T.; Hutchison, G.R.; Murray-Rust, P.; Rzepa, H.; Steinbeck, C; Wegner, J.; Willighagen, E.L. “The Blue Obelisk—Interoperability in chemical informatics.” Journal of Chemical Information and Modeling 2006 Web Release Date: 22-Feb-2006; DOI: 10.1021/ci050400b

Bibliography: Articles (cont’d) Jónsdóttir, S.O.; Jorgensen, F.S.; Brunak, S. “Prediction methods and databases within chemoinformatics: emphasis on drugs and drug candidates.” Bioinformatics 2005 May 15; 21(10): 2145-60. Jorgensen, William L. “The many roles of computation in drug discovery.” Science March 19, 2004, 303, 1813-1818. Kauffman, Thom. “Profile.” [interview] LiveWire, March 2005, 7.3; http://pubs.acs.org/4librarians/livewire/2006/7.3/profile.html Murray-Rust, Peter S.; Mitchell, John B.O.; Rzepa, Henry S. “Communication and re-use of chemical information in bioscience.” BMC Bioinformatics 2005, 6, 180. Murray-Rust, Peter; Mitchell, John B.O.; Rzepa, Henry S. “Chemistry in bioinformatics.” BMC Bioinformatics 2005, 6, 141-144. Povolna, Vera; Dixon, Scott; Weininger, David. “Cabinet—Chemical and Biological Informatics NETwork.” in: Oprea, Tudor I., ed. Chemoinformatics in Drug Discovery. Weinheim: Wiley-VCH, 2004, 241-269.

Bibliography: Articles (cont’d) Salamone, Salvatore. “Hip Hop offers lessons on life sciences data integration.” Bio-IT World February 2006, 36. Scherf Uwe, Ross Douglas T., Waltham Mark, Smith Lawrence H., Lee Jae K., Tanabe Lorraine, Kohn Kurt W., Reinhold William C., Myers Timothy G., Andrews Darren T., Scudiero Dominic A., Eisen Michael B., Sausville Edward A., Pommier Yves, Botstein David, Brown Patrick O., Weinstein John N. “A gene expression database for the molecular pharmacology of cancer.” Nature Genetics 2000, 24, 236-244. Souchelnytskyi, S. "Bridging proteomics and systems biology: What are the roads to be traveled?" Proteomics 2005 (November), 5(16), 4123-4137. Tetko, Igor V. “Computing chemistry on the web.” Drug Discovery Today November 2005, 10(22), 1497-1500.

Bibliography: Articles (cont’d) Zimmermann, Marc; Thi, Le Thuy Bui; Hofmann, Martin. “Combating illiteracy in chemistry: Towards computer-based chemical structure reconstruction.” ERCIM News January 2005, 60, 40-41. http://www.scai.fraunhofer.de/uploads/media/MZ-ERCIM05_04.pdf Zimmermann, Marc; Fluck, Juliane; Thi, Le Thuy Bui; Kolarik, Corinna; Kumpf, Kai; Hofmann, Martin. “Information extraction in the life sciences: Perspectives for medicinal. chemistry, pharmacology and toxicology.” Current Topics in Medicinal Chemistry 2005, 5(8), 785-796.

Bibliography: Databases Andreeva, A.; Howorth, D.; Brenner, S.E.; Hubbard, T.J.P.; Chothia, C.; Murzin, A.G. “SCOP database in 2004: refinements integrate structure and sequence family data.” Nucleic Acids Research 2004, 32 Database issue D226-D229 doi: 10.1093/nar/gkh039 Chen J, Swamidass SJ, Dou Y, Bruand J, Baldi P. “ChemDB: a public database of small molecules and related chemoinformatics resources.” Bioinformatics. 2005 Nov 15; 21(22): 4133-9. Dunkel, M.; Fullbeck, M.; Neumann, S.; Preissner, R. “SuperNatural: a searchable database of available natural compounds.” Nucleic Acids Research 2006, 34, Database issue D678-D683 doi: 10.1093/nar/gkj132 Gold, Nicola D.; Jackson, Richard M. “A searchable database for comparing protein-ligand binding site for the analysis of structure-function relationships.” Journal of Chemical Information and Modeling 2006, 46(2), 736-742.

Bibliography: Databases (cont’d) Kanehisa, M.; Goto, S.; Hattori, M.; Aoki-Kinoshita, F. Itoh, M.; Kawashima, S.; Katayama, T.; Araki, M; Hirakawa, M. “From genomics to chemical genomics: new developments in KEGG.” Nucleic Acids Research 2006, 34, Database issue D354-D357. doi: 10:1093/nar/gkj102. Kellenberger, Esther; Muller, Pascal; Schalon, Clarire; Bret, Guillaume; Foata, Nicolas; Rognan, Didier. “sc-PDB: An annotated database of druggable binding sites from the Protein Data Bank.” Journal of Chemical Information and Modeling 2006, 46(2), 717-727. Kirwin, J.J.; Shoichet, B.K. “ZINC—A free database of commercially available compounds for virtual screening.” Journal of Chemical Information and Modeling 2005, 45, 177-182. Kouranov, A.; Xie, L. de la Cruz, J.; Chen, L.; Westbrook, J.; Bourne, P.E.; Berman, H.M. “The RCSB PDB information protal for structural genomics.” Nucleic Acids Research 2006, 34, Database issue D302-D305 doe: 10:1093/nar/gkj120 Kumar, M.D.S.; Gromiha, M.M. “PINT: Protein-protein interactions thermodynamic database.” Nucleic Acids Research 2006, 34 Database issue D195-D198 doi: 10.1093/nar/gkj017

Bibliography: Databases (cont’d) Lo Conte, L.; Brenner, S.E.; Hubbard, T.J.P.; Chothia, C.; Murzin, A.G. “SCOP database in 2002: refinements accommodate structural genomics.” Nucleic Acids Research 2002, 30(1): 264-267. Murzin, A.G.; Brenner, S.E.; Hubbard, T.; Chothia, C. “SCOP: A structural classification of proteins database for the investigation of sequences and structures.” Journal of Molecular Biology 1995, 247, 536-540. Okuno, Y.; Yang, J.; Taneishi, K.; Yabuuchi, H.; Tsujimoto, G. “GLIDA: GPCR-ligand database for chemical genomic drug discovery.” Nucleic Acids Research 2006, 34, Database issue D673-D677 doi: 10.1093/nar/gkj028. Pearl F, Todd A, Sillitoe I, Dibley M, Redfern O, Lewis T, Bennett C, Marsden R, Grant A, Lee D, Akpor A, Maibaum M, Harrison A, Dallman T, Reeves G, Diboun I, Addou S, Lise S, Johnston C, Sillero A, Thornton J, Orengo C. The CATH Domain Structure Database and related resources Gene3D and DHS provide comprehensive domain family information for genome analysis.” Nucleic Acids Research. 2005, 33 Database Issue D247-D251.

Bibliography: Databases (cont’d) Wheeler, D.L. et al. “Database resources of the National Center for Biotechnology Information.” Nucleic Acids Research 2006, 34 Database Issue D173-D180 doi: 10.1093/nar/gkj158 Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey, Jennifer. “DrugBank: a comprehensive resource for in silico drug discovery and exploration.” Nucleic Acids Res. 2006 Jan 1;34(Database issue): D668-72.

Biotech Validation Suite for Protein Structures Send the server a PDB file Server provides a comprehensive check of the protein, including: Atomic volume analysis Full geometric analysis NMR restraint data http://biotech.ebi.ac.uk:8400/

Knowledge-Driven Bioinformatics Enhanced with Chemistry

ToxTree An in silico toxicology prediction suite Based on the CDK toolkit Built on CML Released as OpenSource under the GPL Standalone PC software User Manual: http://ecb.jrc.it/DOCUMENTS/QSAR/TOXTREE/toxTree_user_manual.pdf

Tools for Genomic and Proteomic Scientists vis-à-vis Cell Biology (Gagna et al.) Tools to fully exploit the techniques in cellular biology Light microscopy for high resolution images Fractionation of cells into basic components via ultracentrifugation Analysis of individual cells through flow cytometry LCM, normal and diseased TMAs (tissue microarrays), quantitative computer image analysis, cell micromanipulation, and high-throughput microscopy

InChI Generation on the Web The following websites provide the facility to generate InChIs: www.acdlabs.com/download/chemsk.html ACD/Labs' freely available structure-drawing program ChemSketch includes the facility to generate InChIs from drawn structures. pubchem.ncbi.nlm.nih.gov/edit/ PubChem Server Side Structure Editor v1.8 includes a facility for generating InChIs as you draw the structure.

Advances in Macromolcular Crystallography by CCG More protein structures available now Use of 3D info in bioinformatics makes functional inferences more dependable CCG Structural Family Database distributed with MOE Includes fold detection methodology to ID structurally similar proteins Simultaneous sequence and structural alignment of large collections of proteins 3D structural family analysis for insight into conserved geometry, water molecules, salt bridges, hydrogen bonds, hydrophobic contacts, and disulfide bonds

CCG’s Cheminformatics Offerings MOE Molecular Database Mo lecular Descriptors calculated and used for classification, clustering, filtering, and predictive model construction QSAR/QSPR Predictive Modeling Diversity and Similarity Searching High Throughput Conformational Search 3D Pharmacophore Search

Components of the Semantic Web for Chemistry XML – eXtensible Markup Language RDF – Resource Description Framework RSS – Rich Site Summary Dublin Core – allows metadata-based newsfeeds OWL – for ontologies BPEL4WS – for workflow and web services Murray-Rust et al. Org. Biomol. Chem. 2004, 2, 3192-3203.

Web Services Integration Projects: Biosciences myGrid http://www.mygrid.org.uk/ BIOPIPE http://biopipe.org/ BioMOBY http://biomoby.org/

BIOT 2006 Major themes, areas and suggested topics include - Bio-molecular and Phylogenetic Databases - Molecular Evolution and Phylogenetic analysis - Drug Delivery Systems - Bio-Ontology and Data Mining - Sequence Search and Alignment - Microarray Analysis - System Biology - Pathway analysis - Identification and Classification of Genes - Protein Structure Prediction and Molecular Simulation - Functional Genomics - Proteomics - Tertiary structure prediction - Drug Docking - Gene Expression Analysis - Biomedical Imaging

Proteomics: What is it? Proteomics is the study of protein expression, regulation, modification, and function in living systems for understanding how living systems use proteins. Using a variety of techniques, proteomics can be used to study how proteins interact within a system, or how proteins change due to applied stresses. Requires advanced measurement techniques, especially separations and mass spectrometry

Proteomics Needs Informatics for: Locating peaks in 2 or more dimensions MS/MS spectra interpretation Protein/Peptide quantification Peptide detectability Experimental data  Biological information enzyme or pathway regulation disease susceptibility drug efficacy