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

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Presentation on theme: "Drug Discovery Grid -- A real grid application Zhang Wenju, Shen Jianhua Shanghai Institute of Materia Medica, CAS Shanghai Jiaotong University Jiangnan."— Presentation transcript:

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 UK e-Science AHM 2005

2 UK e-Science AHM 05, Nottingham, Sept , 2005 Agenda 1.DDGrid Introduction 2.DDGrid Architecture 3.DDGrid Resources 4.DDGrid Demo

3 UK e-Science AHM 05, Nottingham, Sept , 2005 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 UK e-Science AHM 05, Nottingham, Sept , 2005 Process of Drug Discovery and Design 2-3 years 3-4 years Random Screening Random Screening 10, 000 ~ 20, , 000 ~ 20, 000 Compounds Random Screening Random Screening 10, 000 ~ 20, , 000 ~ 20, 000 Compounds Drug Candidate Pre-clinicPre-clinic Clinic (phase I, II, III) Clinic MarketMarket 2-3 years Time: years Time: years Money: several billion dollars Money: several billion dollars Computer -Aid Drug Design Leads and Opt. Leads and Opt. Leads and Opt. Leads and Opt.

5 UK e-Science AHM 05, Nottingham, Sept , 2005 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 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Architecture

7 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Architecture

8 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Architecture

9 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Workflow Job Submit Global Server (Monitoring, Work Pool, Resource Manag., Assimilate of Result) ID and Result Return Slave Server (Local Resource Manag., Monitoring, Local Work Pool, Assimilate of Result) Return of Result, New job request Job Dispatch Computational Client (Docking) Job Dispatch Return of Result, New job request xml

10 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid security 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 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid message passing i686-pc-linux-gnu … …

12 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid message passing No work available Ddg sss … … … …

13 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid message passing … 0 tabfile 1 infile 2 sphfile -business

14 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid message passing … Ddg gridapp gridapp/gridapp_2.19_i686-pc-linux-gnu … …

15 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Resources Computational and Data Resources Integration Resources aggregated (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 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Resources DDGrid Apps. 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 Fixed CDB start Input File Pre process Dock Drug-like Analysis New CDB Exper iment end CDB Gen. CDB Para.

17 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Resources 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 UK e-Science AHM 05, Nottingham, Sept , 2005 Deployed commercial CDB (appr.700,000) Name of Database Description Specs Provides about 230,000 compounds CMC-3D Provides 3D models and important biochemical properties (including drug class, logP, and pKa values) for over 8,400 pharmaceutical compounds. ACD-3D Provides 200,000 3D compounds commercial available NCI-3D 213,000compounds with 2D information from the National Cancer Institute CNPD Collected 12,000 Chinese natural products with chemical structure TCMD With 9127 compounds and 3922 herbs

19 UK e-Science AHM 05, Nottingham, Sept , 2005 VendorNum. of Mol.VendorNum. of Mol. ACB-Eurochem98603Maybridge53042 Ambinter533866Nanosyn68317 Asinex293385National Cancer Institute ChemBridge562624Otava ChemDiv361859Peakdale9632 ComGenex38590Pharmeks Enamine533111PubChem IBScreen452728Ryan Scientific64205 InterChim288882Sigma-Aldrich49022 KeyOrganics22294Specs Life Chemicals44762TimTec appr. 3,300,000 compounds

20 UK e-Science AHM 05, Nottingham, Sept , 2005 CDB example CNPD-China Natural Products Database

21 UK e-Science AHM 05, Nottingham, Sept , 2005 CDB example CNPD CNPD: The first comprehensive source of chemical, structural and bibliographic data on almost all known natural products in China. CNPD serves 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 UK e-Science AHM 05, Nottingham, Sept , 2005 CDB example CNPD

23 UK e-Science AHM 05, Nottingham, Sept , 2005 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 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 UK e-Science AHM 05, Nottingham, Sept , 2005 CDB example TCMD

25 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid applications in reality SIMM carried out anti-SARS and anti-diabetes drug research using the DDGrid 1.Anti-SARS drug research 2.Anti-diabetes drug research

26 UK e-Science AHM 05, Nottingham, Sept , 2005 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 x and PCT patent pi Research on Anti-SARS medicine

27 UK e-Science AHM 05, Nottingham, Sept , 2005 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 800, , Research on anti-diabetes medicine

28 UK e-Science AHM 05, Nottingham, Sept , 2005 New anti-diabetes drug Current Progress 1. Applied for patent X and PCT patent 2. Security testing and pre-clinic research

29 UK e-Science AHM 05, Nottingham, Sept , 2005 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 UK e-Science AHM 05, Nottingham, Sept , 2005 Collaboration Selected Users of DDGrid

31 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Demo Demo

32 UK e-Science AHM 05, Nottingham, Sept , 2005 DDGrid Web Portal

33 UK e-Science AHM 05, Nottingham, Sept , 2005 Test Case 1 Virtual Screening from 20,000 compounds Involved Sites: Shanghai Inst. of M. M. (SIMM) Alpha Cluster (32CPU) Beijing Mol. Ltd. Sunway Cluster (224CPU) The Univ. of Hong KongGideon Cluster (16CPU) Shanghai SuperComp. CentreDawning 4000A Dalian Univ. of Tech.Dawning 4000A London e-Science CentreMars Cluster Time consumed: 5946 sec appr. 99 min Data Sets (CDB) Specs

34 UK e-Science AHM 05, Nottingham, Sept , 2005 Job scheduling

35 UK e-Science AHM 05, Nottingham, Sept , 2005 Visualisation of Docking Result

36 UK e-Science AHM 05, Nottingham, Sept , 2005 CDB Structure Search

37 UK e-Science AHM 05, Nottingham, Sept , 2005 CDB Structure Search

38 UK e-Science AHM 05, Nottingham, Sept , 2005 CDB Structure Search

39 UK e-Science AHM 05, Nottingham, Sept , 2005 Demo

40 UK e-Science AHM 05, Nottingham, Sept , 2005 Demo

41 UK e-Science AHM 05, Nottingham, Sept , 2005 Demo

42 UK e-Science AHM 05, Nottingham, Sept , 2005 Demo

43 UK e-Science AHM 05, Nottingham, Sept , 2005 Demo

44 UK e-Science AHM 05, Nottingham, Sept , 2005 Acknowledgements This work has been supported by National High-Tech Research and Development Project of China (863 program), under contract No. 2004AA 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 UK e-Science AHM 05, Nottingham, Sept , 2005 Thank you Q&A


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