Development of a web-based compound database system at

Development of a web-based compound database system at TEIJIN Pharma: Integration of the compound database and other existing systems TEIJIN PHARMA LIMITED Sogawa Ryo (Medicinal Chemist) 14 June, 2007

About TEIJIN Group Teijin Limited, established in 1918, was the first Japanese company to produce rayon, and has remained an innovator and leader in the development and commercialization of fibers. Since then, Teijin has capitalized on its expertise in fibers to diversify into other fields. Today, Teijin’s operations encompass four segments: 1. Fibers and Textiles 2. Films and Plastics 3. Pharmaceuticals and Home Health Care 4. Newly Developed Businesses At present, Teijin is utilizing its proprietary technologies to expand into promising new areas, notably health-care products and services, advanced materials and information media.

Organization of the Teijin Group (as of October, 2003) Teijin Group President &CEO Toru Nagashima TEIJIN FIBERS LIMITED (Textile Fibers) TEIJIN TECHNO PRODUCTS LIMITED (Industrial Fibers) NI TEIJIN SHOJI CO. , LTD. (Fiber Products Marketing) TEIJIN FILMS LIMITED, TEIJIN DUPONT FILM GLOBALJVS (Film) TEIJIN CHEMICALS LIMITED (Plastics) TEIJIN PHARMA LIMITED Pharmaceutical Business Unit & Home Healthcare Business Unit INFOCOM CORPORATION (IT Business) New Business Development Business Group

Pharmaceutical Products In House Products Indication Onealfa Alfacalcidol (1αOHVD 3) Osteoporosis, Renal Bone Disease Bonalfa Tacalcitol (1α, 24(OH)2 VD 3) Psoriasis (Ointment, Cream, Lotion and High conc. ointment) Venilon Sulfonated γ-globulin Severe Infectious Diseases Kawasaki Disease Idiopathic Thrombocytopenic Purpura Guillain-Barre Syndrome Anact C Activated Protein C Deficiency Rhinocort Steroid Powder Spray (Nasal) Allergic Rhinitis Aftach Mucosa Adhesive Steroid Tablet (Mouth) Aphthous Stomatitis Salcoat Steroid Powder Spray (Mouth) Diffuse Aphthous Stomatitis Antup ISDN Patch Angina Pectoris

Pharmaceutical Products License-in Products Indication Products from B. Ingelheim Laxoberon Sodium Picosulfate Laxative Atrovent HFA Ipratropium Bromide Asthma, COPD Mucosolvan Ambroxole HCl Expectorant Spiropent Clenbuterol HCl Asthma, Urinary Incontinence Product from Merck (Gentili) Teiroc Alendronate, iv Hypercalcemia of Malignancy Bonalon Alendronate, po Osteoporosis Product from Fresenius Saliveht Artificial Saliva Dry Mouth Product from KAKETSUKEN Bolheal Fibrinogen Powder Adhesion/Closure of Tissue Product from Morishita Jintan Solmiran Ethyl Icosapentate Peripheral Arterial Disease

Research & Development • R&D Investment 15% of the turnover • Research Institute: Founded in 1974 at Hino-city, Tokyo GLP Safety Evaluation Center (1982) New Pharmacological Research Center (1994) New Pharmacokinetic Research Center (1998) New Pharmaceutical Research Center (1998) ca. 300 Researchers • Clinical Development Tokyo Office, ca 80 staff Teijin America, Inc. (Princeton, NJ, USA)

Why TPM Started Re-building Cheminformatics system?

Background l Increasing Data in Early Research Stage Increasing number of compounds • Wide variety of parameters （e. ADME、e. Tox・・・） • l Needs for Efficient Feed-back • l Diversified Researchers are Involved • l Speeding-up the work flow cycle Researchers with diversified background Various Data in Various Formats Biological activity, ADME, Safety, . . . • Excel, Oracle DB, Word document. . . •

Increasing Numbers of Compounds 10 times increase in 10 years Clear contribution of combinatorial chemistry (red in figure)

Wide Variety of Parameters l Increasing number of parameters from “wet” experiment • l Optimization of one parameter (activity) Simultaneous optimization of multiple parameters Computational parameters • Tens of chemical descriptors are available for SAR analysis The size of data researchers have to consider is (#compounds) x (#parameters)!!

Work Flow Cycle Accelrys software Chemistry Academic software ISIS/Base >> JChem （Web Browser） Accord for Excel Analytical Design Drug Discovery work flow Data Analysis HTS Spotfire Biology ADMET Activity. Base

Requests to Cheminformatics Tools (from Researchers) Interactive browsing and analysis on multiple compounds/parameters information l Stable handling of huge data l Easy registration and access to various data source l • l No special skill needed Satisfy different needs of researchers of different background

Problems l Platform migration from ISIS to Isentris l Continuity of support for ISIS/Host was unclear l Limitation by ISIS/Base（ISIS/PL） development environment l Separated networks l TEIJIN global Network（for office • e-mail, Handling office documents work） l Research institute LAN（for laboratory work） • Cheminformatics、Computational Chemistry • Laboratory Automation l License costs l Increasing number of named user licenses

Chemical DB Migration

Aim l Aim • Re-building of compounds DB system without ISIS l • ISIS　→　？？？ Data can be registered/browsed from individual clients for each researcher in various sections l Migration to Web-based compound DB system Researcher Web browser Compounds DB Assay DB

The Project Time Line Start of the project Start of development Start of operation ’ 05. 10 ’ 06. 04～ ’ 06. 10～ TPM: 6 chemists 2 assay Examination Infocom: 2 IT of platforms User WG • Structure search • Development Environment Problems -> Specifications • Work flow analysis Design • System structure • Test • User Interface Development • DB contents Introduction 2006/10 New system started • Data migration

Platform Examination l To which platform should we migrate? • Structure search function？ →　speed、accuracy l The system must precisely recognize various complex chemical structures!! Development environment？→　language、OS • Candidates • JChem： l Accord： l Structure. Base： l Chem. Office： l Isentris： l Chem. Axon Accerlys IDBS Cambridge. Soft MDL

Platform Examination l Requirement • • • l Improvement of user accessibility →　Web based system Integration of aplications →　Structure search with SQL Uniform user interface →　Chemical editor Management of all in house compounds→　Precise structure handling Low cost Candidates l l l JChem： Chem. Axon Accord： Accerlys Structure. Base： IDBS Chem. Office： Cambridge. Soft Isentris： MDL

Why JChem? l Advantages of JChem • Affinity with web technology Java l (Future) handling of more diverse data source l • Sufficient basic functions substructure and similarity searching l inserting and modifying data in structure tables l manipulating structures l SDfile, Molfile, SMILES import/export l • Chemical editor Marvin. Sketch : for structure input and modification l Marvin. View : for displaying structures l

JChem - Chemistry Engine l JChem • JChem Base JDBC l Structure search with Java Class　→　Searchable in many DBs（ Oracle, My. SQL, MSSQL Server, MS Access, DB 2, Postgre. SQL etc… ） l JChem. Search searcher = new chemaxon. jchem. db. JChem. Search(); searcher. set. Connection. Handler(ch); searcher. set. Search. Type(JChem. Search. SUBSTRUCTURE) searcher. set. Query. Structure(“c 1 ccccc 1”); searcher. set. Structure. Table(“SCOTT. STRUCTURES”); searcher. run(); int[] results=searcher. get. Results(); • JChem Cartridge for Oracle data cartridge l Structure search with SQL　→　Non- Java environment is possible（ VB, VC++, . NET etc…） l SELECT cd_id FROM scott. jchemtable WHERE jc_contains(smiles, 'CN 1 C=NC 2=C 1 C(=O)N(C)C(=O)N 2 C') = 1; 情報参照先 JChem http: //www. chemaxon. com/jchem/

JChem - Architecture SQL Plus / DB aplication JChem Server Oracle JChem Streams Adapter search engine JChem Cartridge ⑦ JChem Cartridge Engine HTTP JChem Streams ① ⑥ ② JChem Base Search Engine ③ ④ JDBC jc_contains Cache ・・・ JChem Core index table ⑤

Integration of Aplications l DB contents • In house compound DB ISIS/Base remote DB customized using ISIS/PL l Registration of synthesized compounds, corporate ID generation l • • Stock reagent DB l ISIS/Base remote DB customized using ISIS/PL • • main fields： corporate ID, project name, Lot No. , purity, synthetic method etc main fields： container ID, supplier, catalog No. , stocked place, user etc Abase Browser ISIS/Base remote DB customized using ISIS/PL l Browsing Activity Base（Assay / ADME） l

Network ISIS/Base File Server Spot. Fire Server -> Web Browser Activity. Base Documents Analysis files Accord for Excel Chem. Office Teijin Pharma’s Lab Network ISIS/Host Server Accelrys software -> Web Server Academic software Oracle Server ISIS Database -> JChem Database Activity. Base Database Spotfire Database

Work Flow Accelrys software Chemistry Academic software ISIS/Base ->JChem （Web Browser） Accord for Excel Analytical Design Drug Discovery work flow Data Analysis HTS Spotfire Biology ADMET Activity. Base

System Server compound DB system Client JChem Server Standardizer Java Marvin. Sketch Marvin. View Java JChem Base Internet Explorer Tomcat HTTP JDBC Oracle JChem Cartridge HTTP

TELI - TEIJIN PHARMA Laboratory Informatics System TELI TEIJIN PHARMA Laboratory Informatics System l Cheminformatics technologies (mainly chemical DB) has been successfully applied to medicinal chemistry research. As a next step, we are planning to introduce and establish “Laboratory Informatics” technology, which enables us to directly handle “wet” data from various experiments. This system development is the start point of such an approach, and we named this system using the words, “Laboratory Informatics System”.

TELI - TEIJIN PHARMA Laboratory Informatics System

Spotfire Modules for JChem l Spotfire Modules for JChem • An application using Chemistry Framework l Data Provider （DB connecting module） Link to the structure data (. mol format) from Spotfire Server • Integration of structural data and non-structural data • Structure search from Spotfire • Pick up the search result from Spotfire • l Structure Renderer （Structure drawing module） Exchange structure data into EMF（Enhanced Meta File) • Display on screen •

Spotfire Modules for JChem View Structure In Table Structure search Structure Viewer File Exporting

Future Plan l Taking advantage of the Web based system・・・ • Seamless integration with various data sources Chemometric descriptors l Analytic data l Link to non-uniform data(ex. in vivo experiment result) l Documents, reports l • Easy access to data　→　More efficient data feed-back!! l l Additional functions using JChem（Marvin） features • l Cross-database-search by structure / keyword Highlighting structures, Alignment, Clustering Development of new tools which works on other platforms • Structure handling from MSOffice(Excel, Word. . . )

Future Plan Manager Web browser Project Leader Web browser Researcher Web browser Compound DB Assay DB Documents Analytic Data

Conclusion l Client/Server -> Web based application Improvement of accessibility • Easy user interface • Decrease maintenance costs • l In-house development Optimized for in-house workflow • Future development • We are moving into next generation!!