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Drug Discovery Grid -- A real grid application

Drug Discovery Grid -- A real grid application. Zhang Wenju, Shen Jianhua Shanghai Institute of Materia Medica, CAS Shanghai Jiaotong University Jiangnan Institute of Computing The University of Hong Kong. Agenda. DDGrid Introduction DDGrid Architecture DDGrid Application DDGrid Demo.

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Drug Discovery Grid -- A real grid application

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  1. Drug Discovery Grid-- A real grid application Zhang Wenju, Shen Jianhua Shanghai Institute of Materia Medica, CAS Shanghai Jiaotong University Jiangnan Institute of Computing The University of Hong Kong

  2. Agenda • DDGridIntroduction • DDGrid Architecture • DDGrid Application • DDGridDemo

  3. Background Large-scale High-throughput Virtual Screening • in Silico The computational analysis of chemical databases to identify compounds appropriate for a given biological receptor • in Vitro Identification of new compounds showing some activity against a target biological receptor, and the progressive optimization of these leads to yield a compound with improved potency and physicochemical properties in vitro • in Vivo eventually, improved efficacy, pharmacokinetics, and toxicological profiles in vivo.

  4. Process of Drug Discovery and Design Leads and Opt. 2-3 years 2-3 years Random Screening 10, 000 ~ 20, 000 Compounds Pre-clinic Drug Candidate Computer-Aid Drug Design 2-3 years Clinic (phase I, II, III) 3-4 years • Time: 10-12 years • Money: several billion dollars Market

  5. DDGrid overview ◆ Drug Discovery Grid project aims to build a collaboration platform for drug discovery using the state-of-the-art grid computing technology. ◆This project intends to solve large-scale computation and data intensive scientific applications in the fields of medicine chemistry and molecular biology with the help of grid middleware developed by our team. ◆Over one million compounds database with 3-D structure and physicochemical properties are also provided to identify potential drug candidates. Users also can build and maintain their own customized ligand database to share in this grid platform.

  6. User User User Internet Internet Global Server Slave Server Slave Server Slave Server DDGridArchitecture

  7. Resource monitoring, job submit and monitor, input and parameter, result view and download through Web Portal User 终端 终端 Internet Internet Global Server Slave Server Slave Server Slave Server DDGridArchitecture

  8. User User User Internet Internet • Global scheduling • User interface • Resources manag. • Job submit and mon. • Key and cert manag. • Result analysis • visisualiszation • Distributed CDB Global Server 子服务器 Slave Server DDGridArchitecture

  9. User User User • Local job manag. • Local res. manag. • Local CDB manag. • Data en-decrypt • Local result assimilate Internet Internet 主服务器 Slave server slave slave DDGridArchitecture

  10. DDGridWorkflow Job Submit IDand Result Return Global Server (Monitoring, Work Pool, Resource Manag., Assimilate of Result) Return of Result, New job request Job Dispatch xml Slave Server(Local Resource Manag., Monitoring, Local Work Pool, Assimilate of Result) Return of Result, New job request Job Dispatch Computational Client (Docking)

  11. DDGridsecurity 1. PKI-based security 2. All the sites involved should hold a certification issued by our CA 3. All the databases deployed and results are encrypted 4. All the message passing are SSL/TLS-enabled

  12. DDGrid Web Portal

  13. Test Case 1 Virtual Screening from 20,000 compounds Involved Sites: Shanghai Inst. of M. M. (SIMM) Alpha Cluster (32CPU) Beijing Mol. Ltd. SunwayCluster (224CPU) The Univ. of Hong Kong Gideon Cluster (16CPU) Shanghai SuperComp. Centre Dawning 4000A Dalian Univ. of Tech. Dawning 4000A London e-Science Centre Mars Cluster Time consumed: 5946 sec（appr. 99 min） Data Sets (CDB)： Specs

  14. Job scheduling

  15. Visualisation of Docking Result

  16. DDGridmessage passing <scheduler_request> <authenticator>3333</authenticator> <hostid>102</hostid> <rpc_seqno>2401</rpc_seqno> <platform_name>i686-pc-linux-gnu</platform_name> <core_client_major_version>2</core_client_major_version> <core_client_minor_version>19</core_client_minor_version> <idle_ncpu>16</idle_ncpu> <project_disk_usage>5315768.000000</project_disk_usage> <total_disk_usage>68417940.000000</total_disk_usage> <code_sign_key> … </code_sign_key> <projects> <project> <master_url>http://www.ddgrid.ac.cn/ddg/</master_url> <resource_share>100.000000</resource_share> </project> </projects> <result> … </result> … <host_info> … </host_info> </scheduler_request>

  17. DDGridmessage passing <scheduler_reply> <message priority="low">No work available</message> <project_name>Ddg</project_name> <user_name>sss</user_name> <code_sign_key> … </code_sign_key> … <workunit> … </workunit> <preferences> <low_water_days>1.2</low_water_days> <high_water_days>2.5</high_water_days> <disk_max_used_gb>0.4</disk_max_used_gb> <disk_max_used_pct>50</disk_max_used_pct> <disk_min_free_gb>0.4</disk_min_free_gb> … </preferences> … </scheduler_reply>

  18. DDGridmessage passing <workunit> <file_info> <number>0</number> </file_info> <file_info> <number>1</number> </file_info> <file_info> <number>2</number> </file_info> … <file_ref> <file_number>0</file_number> <open_name>tabfile</open_name> </file_ref> <file_ref> <file_number>1</file_number> <open_name>infile</open_name> </file_ref> <file_ref> <file_number>2</file_number> <open_name>sphfile</open_name> </file_ref> <command_line>-business</command_line> </workunit>

  19. DDGridmessage passing … <project> <scheduler_url>http://www.ddgrid.ac.cn/ddg_cgi/cgi</scheduler_url> <master_url>http://www.ddgrid.ac.cn/ddg/</master_url> <project_name>Ddg</project_name> </project> <app> <name>gridapp</name> </app> <file_info> <name>gridapp/gridapp_2.19_i686-pc-linux-gnu</name> <nbytes>260754.000000</nbytes> <max_nbytes>0.000000</max_nbytes> <executable/> <signature_required/> <file_signature> … </file_signature> <url>http://www.ddgrid.ac.cn/ddg/download/gridapp_2.19_i686-pc-linux-gnu</url> </file_info> <file_info> … </file_info> …

  20. DDGridResources Computational and Data Resources Integration Resourcesaggregated SIMM Sunway 32A Cluster Beijing Molecule Inc. Sunway 256P Cluster HKU Gideon 300 Cluster SSC Dawning 4000A LeSC Mars Cluster (Test only) Singapore Poly-tech Univ. Dalian Univ. of Technology Shanghai Jiaotong Univ. Heterogeneous resources OS: IRIX, Digital Unix, Linux(IA32, x86_64) CPU：R12000, Alpha, Pentium, AMD

  21. Fixed CDB start Input File Dock Drug-like Analysis Preprocess New CDB Experiment end CDB Gen. CDB Para. DDGridResources • DDGridApps. • Docking pre-process software • Combimark • 2. Docking software • 1) Dock UCSF • 2) gsDock SIMM • 3. CDB build and maintain S/W • Combilib • 4. AutoDock • 5. AutoGrid • 6. Visualisation • 7. Security-related tools

  22. DDGridResources Chemical Databases (CDB) Each ligand record in a chemical database represents the 3D structural information of a compound. The numbers of compounds in each CDB can be in the order of tens of thousands and the database size be anywhere from tens of megabytes to gigabytes and even terabytes. 1. static databases purchased from commercial chemical company. Available Chemical Directory (ACD) Chinese natural product database (CNPD) SPECS database chemical ADME/T database, etc. 2. dynamic databases made by user own, and deployed automatically.

  23. Deployed commercial CDB (appr.700,000)

  24. appr. 3,300,000compounds

  25. CDB example：CNPD-China Natural Products Database

  26. CDB example：CNPD CNPD:The first and only comprehensive source of chemical, structural and bibliographic data on all known natural products in China. CNPDserves as information sources for chemical, physical and biological properties, literature, they are useful to scientists within the pharmaceutical industry. CNPD can be searched in flexible ways: structure, sub-structure, name, molecular formula, molecular weight, CAS register number, category, etc. CNPD:Traditional Chinese Medicine (TCM) applications are pre-indexed in CNPD to provide hints for lead compounds discovery.

  27. CDB example：CNPD

  28. CDB example：TCMD TCMD-Traditional Chinese Medicine Database TCMD is a bibliographical database of approximately 20,000 records with abstracts of TCM articles. Relevant articles are selected from among 150-200 journals from Mainland China, Taiwan, and Hong Kong (most of them are Chinese); English abstracts are written for the selected articles and other pertinent information is translated into English.

  29. CDB example：TCMD

  30. DDGridapplications in reality • SIMM carried out anti-SARS and anti-diabetes drug research using the DDGrid • Anti-SARS drug research • Anti-diabetes drug research

  31. Research on Anti-SARS medicine Virtual screening from Comprehensive Medicinal Chemistry-3D(CMC-3D)database which contains 7,900 compounds, found that cinanserin have distinct anti-SARS effect Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, Germany Research Department, Cantonal Hospital St Gallen, Switzerland “Basically your inhibitor turned out to be the best compound we have tested so far! ” Have applied for domestic patent 03129071.xand PCT patent pi034248

  32. 800,000 200,000 138 14 Research on anti-diabetes medicine Found an anti-diabetes lead better than Rosiglitazone. by targeting on PPAR，through virtual screening, optimization design and synthesis and biology and pharmacology testing CADD process

  33. Research on anti-diabetes medicine 2.4 m 400 t 10 t composite design virtual screening virtual screening 500 manually screening 85 synthesis 142 48 KD<1 mM 22 KD<0.1mM protein testing 76 protein testing 48 KD<100mM cell testing 8 animal testing 4 1 comprehensive evaluation

  34. New anti-diabetes drug Current Progress 1. Applied for patent 200410016460.X，and PCT patent 2. Security testing and pre-clinic research

  35. What does the DDGrid provide？ 1、 Drug Design Collaboration Platform Large-scale Virtual Screening platform sharing large CDB 2、Computational Resources Sharing SIMM/SSC/HKU/Mol. Ltd/SJTU/DUT 3、Data Resources Sharing pre-deployed commercial CDB (ACD/CNPD …) sharing self-made CDB 4、Medicinal chemistry text and structure search 5、Customization and Extension

  36. Collaboration Selected Users of DDGrid

  37. DDGridDemo Demo http://www.ddgrid.ac.cn

  38. Demo

  39. Demo

  40. Demo

  41. Demo

  42. Demo

  43. Thank you！ Q&A

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