Overview of Chemical Informatics and Cyberinfrastructure Collaboratory

1. Overview of Chemical Informatics and Cyberinfrastructure Collaboratory March 15 2007 Geoffrey Fox Computer Science, Informatics, Physics Pervasive Technology Laboratories Indiana University Bloomington IN 47401 gcf@indiana.edu http://www.infomall.org http://www.chembiogrid.org

2. Indiana University Summary Indiana University is focusing on two major areas: • Creating a comprehensive, easily accessible infrastructure for chemoinformatics toolsand data sources, linked with PubChem and made available as web services, and partnering with screening centers and other users to demonstrate how this infrastructure can be usefully applied • Infrastructure can include any tools, not just ours (commercial/open source, chemoinformatics, bioinformatics, and so on) • New, custom applications can be built quickly using existing services in a similar way to Google Maps and other “web 2.0” resources • Being a central hub of chemoinformatics education, including offering distance courses on chemoinformatics theory and techniques, practical workshops on using chemoinformatics resources, and freely available web-based educational resources • We currently offer a Ph.D, M.S. and graduate certificate (distance) in chemical informatics • Distance education program allows you to “pick and choose” courses to meet educational needs: certificate is awarded on completion of four courses

3. CICC Senior Personnel • Peter T. Cherbas • Mehmet M. Dalkilic • Charles H. Davis • A. Keith Dunker • Kelsey M. Forsythe • John C. Huffman • Malika Mahoui • Daniel J. Mindiola • Santiago D. Schnell • William Scott • Craig A. Stewart • David R. Williams • Geoffrey C. Fox • Mu-Hyun (Mookie) Baik • Dennis B. Gannon • Kevin E. Gilbert • Rajarshi Guha • Marlon Pierce • Beth A. Plale • Gary D. Wiggins • David J. Wild • Yuqing (Melanie) Wu From Biology, Chemistry, Computer Science, Informatics at IU Bloomington and IUPUI (Indianapolis)

4. Chemical Informatics and Cyberinfrastucture Collaboratory Funded by the National Institutes of Health www.chembiogrid.org CICC CICC CICC Combines Grid Computing with Chemical Informatics Large Scale Computing Challenges Science and Cyberinfrastructure CICC is an NIH funded project to support chemical informatics needs of High Throughput Cancer Screening Centers. The NIH is creating a data deluge of publicly available data on potential new drugs. Chemical Informatics is non-traditional area of high performance computing, but many new, challenging problems may be investigated. NIH PubMed DataBase OSCAR Text Analysis Cluster Grouping Toxicity Filtering Docking . Initial 3D Structure Calculation OSCAR-mined molecular signatures can be clustered, filtered for toxicity, and docked onto larger proteins. These are classic “pleasingly parallel” tasks. Top-ranking docked molecules can be further examined for drug potential. Chemical informatics text analysis programs can process 100,000’s of abstracts of online journal articles to extract chemical signatures of potential drugs. Molecular Mechanics Calculations Big Red (and the TeraGrid) will also enable us to perform time consuming, multi-stepped Quantum Chemistry calculations on all of PubMed. Results go back to public databases that are freely accessible by the scientific community. • CICC supports the NIH mission by combining state of the art chemical informatics techniques with • World class high performance computing • National-scale computing resources (TeraGrid) • Internet-standard web services • International activities for service orchestration • Open distributed computing infrastructure for scientists world wide NIH PubChem DataBase Quantum Mechanics Calculations IU’s Varuna DataBase POVRay Parallel Rendering Indiana University Department of Chemistry, School of Informatics, and Pervasive Technology Laboratories

5. OSCAR Document Analysis InChI Generation/Search Computational Chemistry (Gamess, Jaguar etc.) Varuna.net Quantum Chemistry Grid Services Service Registry Job Submission and Management Local Clusters IU Big Red TeraGrid, Open Science Grid Portal Services RSS Feeds User Profiles Collaboration as in Sakai CICC Web Service Infrastructure

6. Web Service Locations Web Service Locations Cambridge University • InChi generation / search • CMLRSS • OpenBabel Cambridge University • InChi generation / search • CMLRSS • OpenBabel Indiana University • Clustering • VOTables • OSCAR3 • Toxicity classification • Database services Indiana University • Clustering • VOTables • Toxicity classification • Database services • Statistics services VCC Laboratory • ALogPS NCI • CSLS University of Cologne • NMRShiftDB

7. Where Does The Functionality Come From? University of Michigan • PkCell Cambridge University • InChi generation / search • OSCAR DigitalChemistry • BCI fingerprints • DivKMeans gNova Consulting NIH • PubChem • PubMed CDK • Cheminformatics European Chemicals Bureau • ToxTree toxicity predictions OpenEye • Docking R Foundation • R package Indiana University • VOTables • NCI DTP predictions • Database services

8. CICC Infrastructure Vision • Drug Discovery and other academic chemistry and pharmacologyresearch will be aided by powerful modern information technology ChemBioGrid set up as distributed cyberinfrastructure in eScience model • ChemBioGrid will provide portals (user interfaces) to distributed databases, results of high throughput screening instruments, results of computational chemical simulations and other analyses • ChemBioGrid will provide services to manipulate this data and combine in workflows; it will have convenient ways to submit and manage multiple jobs • ChemBioGrid will include access to PubChem, PubMed, PubMed Central, the Internet and its derivatives like Microsoft Academic Live and Google Scholar • The services include open-source software like CDK, commercial code from vendors from BCI, OpenEye, Gaussian and Google, and any user contributed programs • ChemBioGrid will define open interfaces to use for a particular type of service allowing plug and play choice between different implementations

9. Cheminformatics Education at IU • Linked to bioinformatics in Indiana University’s School of Informatics • School of Informatics degree programs BS, MS, PhD • Programs offered at both the Indianapolis (IUPUI) and Bloomington (IUB) campuses • Bioinformatics MS and track on PhD • Chemical InformaticsMS and track on PhD • Informatics Undergraduates can choose a chemistry cognate (change to Life Sciences ) • PhD in Informatics started in August 2005 and offers tracks in • bioinformatics; chemical informatics; health informatics; human-computer interaction design; social and organizational informatics; more to come! • Good employer interest but modest student understanding of value of Cheminformatics degree • 3 core courses in Cheminformatics plus seminar/independent studies • Significant interest in distance education version of introductory Cheminformatics course (enrollment promising in Distance Graduate Certificate in Chemical Informatics)

10. Example: Spreading chemoinformatics education with CIC courseshare • We have partnered with the University of Michigan to offer our introductory chemoinformatics (I571) course concurrently at Indiana University and the University of Michigan as a CIC courseshare, so UM pharmacy, chemistry and engineering students can be trained in chemoinformatics techniques for course credit at UM • In addition, individual students in academia, government, and small and large life science companies have taken the class remotely from all over the country for credit towards the graduate certificate • Uses mixture of web conferencing (Breeze), videoconferencing, and online resources for maximum flexibility • Minimally all that is required is a telephone and internet-connected PC • Students can replay any of the classes using just a regular PC • Most recent course wiki is available at http://cheminfo.informatics.indiana.edu/djwild/I571_2006_wiki Giving a class remotely to UM students with video and web conferencing

11. MLSCN Post-HTS Biology Decision Support Percent Inhibition or IC50 data is retrieved from HTS Grids can link data analysis ( e.g image processing developed in existing Grids), traditional Chem-informatics tools, as well as annotation tools (Semantic Web, del.icio.us) and enhance lead ID and SAR analysis A Grid of Grids linking collections of services atPubChem ECCR centers MLSCN centers Workflows encoding plate & control well statistics, distribution analysis, etc Question: Was this screen successful? Workflows encoding distribution analysis of screening results Question: What should the active/inactive cutoffs be? Question: What can we learn about the target protein or cell line from this screen? Workflows encoding statistical comparison of results to similar screens, docking of compounds into proteins to correlate binding, with activity, literature search of active compounds, etc Compounds submitted to PubChem PROCESS CHEMINFORMATICS GRIDS

12. Example HTS workflow: finding cell-protein relationships A protein implicated in tumor growth with known ligand is selected (in this case HSP90 taken from the PDB 1Y4 complex) The screening data from a cellular HTS assay is similarity searched for compounds with similar 2D structures to the ligand. Docking results and activity patterns fed into R services for building of activity models and correlations LeastSquares Regression RandomForests NeuralNets Similar structures are filtered for drugability, are converted to 3D, and are automatically passed to the OpenEye FRED docking program for docking into the target protein. Once docking is complete, the user visualizes the high-scoring docked structures in a portlet using the JMOL applet. Similar structures to the ligand can be browsed using client portlets.

13. Example: PubDock • Database of approximately 1 million PubChem structures (the most drug-like) docked into proteins taken from the PDB • Available as a web service, so structures can be accessed in your own programs, or using workflow tools like Pipeline Polit • Several interfaces developed, including one based on Chimera (below) which integrates the database with the PDB to allow browsing of compounds in different targets, or different compounds in the same target • Can be used as a tool to help understand molecular basis of activity in cellular or image based assays

14. Example: R Statistics applied to PubChem data • By exposing the R statistical package, and the Chemistry Development Kit (CDK) toolkit as web services and integrating them with PubChem, we can quickly and easily perform statistical analysis and virtual screening of PubChem assay data • Predictive models for particular screens are exposed as web services, and can be used either as simple web tools or integrated into other applications • Example below uses DTP Tumor Cell Line screens - a predictive model using Random Forests in R makes predictions of probability of activity across multiple cell lines (available at http://rguha.ath.cx/~rguha/ncidtp/dtp)

15. Varuna environment for molecular modeling (Baik, IU) Chemical Concepts Researcher Papers etc. Experiments ChemBioGrid Simulation ServiceFORTRAN Code, Scripts DB ServiceQueries, Clustering,Curation, etc. ReactionDB QM Database Condor PubChem, PDB,NCI, etc. QM/MM Database TeraGridSupercomputers“Flocks”

16. Methods Development at the CICC • Tagging methods for web-based annotation exploiting del.icio.us and Connotea • Development of QSAR model interpretability and applicability methods • RNN-Profiles for exploration of chemical spaces • VisualiSAR - SAR through visual analysis • See http://www.daylight.com/meetings/mug99/Wild/Mug99.html • Visual Similarity Matrices for High Volume Datasets • See http://www.osl.iu.edu/~chemuell/new/bioinformatics.php • Fast, accurate clustering using parallel Divisive K-means • Mapping of Natural Language queries to use cases and workflows • Advanced data mining models for drug discovery information • Physics-based Scoring Algorithms

17. What Do You Get in a Web Service? • WSDL for all services available • Collected on a web page • Available in a UDDI repository • Javadocs or plain text descriptions • Source code and associated unit tests • Various client examples • Web pages (via PHP) • Python • Chimera

18. Web Service Vision • Web services provide a neutral approach to exposing functionality • You can utilize them in • Workflow tools – Pipeline Pilot, Taverna, XBaya • Desktop clients – Chimera, custom • Web pages • They can be located anywhere • On your desktop • Intranet • Internet

19. Web Service Vision • Literally anything can be made into a web service • Libraries • Standalone programs • Commerical code • Open-source code

20. RSS Feeds • Provide access to DB's via RSS feeds • Feeds include 2D/3D structures in CML • Viewable in Bioclipse, Jmol as well as Sage etc. • Two feeds currently available • SynSearch – get structures based on full or partial chemical names • DockSearch – get best N structures for a target

21. R, CDK & PubChem • Goals • Access cheminformatics from within R • Access PubChem data from within R • rcdk package allows to do cheminformatics within R using CDK functionality • rpubchem provides access to PubChem compound data and bioassay data • Searchable via assay ID, keywords • J. Stat. Soft, 2007, 18(6)

22. Databases • Most of our databases aim to add value to PubChem or link into PubChem • We maintain a local mirror for testing, data mining • 3D structures (MMFF94) • Searchable by CID, SMARTS, 3D similarity • Docked ligands (FRED) • 906K drug-like compounds into 7 ligands • Will eventually cover ~2000 targets

23. (Cheminformatics) Algorithm Development • Goals • Focus on interpretability and applicability • Devise novel approaches to clustering problems • Investigate the utility of low dimensional representations for a variety of problems • Examples • Ensemble feature selection (JCIM, in press) • Cluster counting with R-NN curves (in revision)

24. Chemical Data Mining • Working on screening data with Scripps, FL • Random forests (modeling & feature selection) • Naïve Bayes (modeling) • Identifying features indicative of toxicity • Domain applicability • NCI DTP Cell line activity predictions • Random forest models for 60 cell lines • All available as • downloadable R models • web services (supply SMILES, get prediction) with web page clients