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Drug Discovery Grid -- A real grid application

UK e-Science AHM 2005. 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

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Drug Discovery Grid -- A real grid application

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  1. UK e-Science AHM 2005 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 Resources • 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 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 P2P and 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. DDGridArchitecture

  7. DDGridArchitecture

  8. DDGridArchitecture

  9. 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)

  10. 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

  11. 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>

  12. 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>

  13. 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>

  14. 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> …

  15. DDGridResources Computational and Data Resources Integration Resourcesaggregated (8 sites, 5 cities) SIMM Sunway 32A Cluster Beijing Molecule Inc. Sunway 256P Cluster HKU Gideon 300 Cluster SSC Dawning 4000A LeSC Mars Cluster (Test only) Shanghai Jiaotong Univ. IBM e1350 cluster Singapore Poly-tech Univ. Rock cluster Dalian Univ. of Technology Dawning 4000A Heterogeneous resources OS: IRIX, Digital Unix, Linux(IA32, x86_64) CPU：R12000, Alpha, Pentium, AMD

  16. Fixed CDB start Input File Dock Drug-like Analysis Preprocess New CDB Experiment end CDB Gen. CDB Para. DDGridResources DDGridApps. 1. 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 & structure search 7. Security-related tools

  17. 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.

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

  19. appr. 3,300,000compounds

  20. CDB example：CNPD-China Natural Products Database

  21. CDB example：CNPD CNPD:The first comprehensive source of chemical, structural and bibliographic data on almost 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.

  22. CDB example：CNPD

  23. 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.

  24. CDB example：TCMD

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

  26. 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

  27. 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

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

  29. 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 …) shared self-made CDB 4、Medicinal chemistry text and structure search 5、Customization and Extension

  30. Collaboration Selected Users of DDGrid

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

  32. DDGrid Web Portal

  33. 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

  34. Job scheduling

  35. Visualisation of Docking Result

  36. CDB Structure Search

  37. CDB Structure Search

  38. CDB Structure Search

  39. Demo

  40. Demo

  41. Demo

  42. Demo

  43. Demo

  44. Acknowledgements This work has been supported by National High-Tech Research and Development Project of China (863 program), under contract No. 2004AA104270 Many thanks to generously resource providers: SIMM HKU SJTU Molecule Ltd. SSC DLUT Involved Persons: Shen Jianhua Ma Fanyuan Zhang Jun Zhang Wenju Chang Yan Chen Shudong Du Xuefeng Li Zhuhua Liu Fei Wan Ju Jiang Maojun …

  45. Thank you！ Q&A

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