DDGrid Grid Asia 20050622

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: 

Agenda DDGrid Introduction DDGrid Architecture DDGrid Application DDGrid Demo

Background: 

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.

Process of Drug Discovery and Design: 

Process of Drug Discovery and Design 2-3 years 3-4 years 2-3 years 2-3 years Time: 10-12 years Money: several billion dollars Computer-Aid Drug Design

Slide5: 

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.

DDGrid Architecture: 

DDGrid Architecture

DDGrid Architecture: 

DDGrid Architecture

DDGrid Architecture: 

DDGrid Architecture

DDGrid Architecture: 

DDGrid Architecture

DDGrid Workflow: 

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

DDGrid security: 

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

Slide12: 

DDGrid Web Portal

Test Case 1: 

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 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

Slide14: 

Job scheduling

Slide15: 

Visualisation of Docking Result

DDGrid message passing: 

DDGrid message 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>

DDGrid message passing: 

DDGrid message 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>

DDGrid message passing: 

DDGrid message 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>

DDGrid message passing: 

DDGrid message 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> …

DDGrid Resources: 

DDGrid Resources Computational and Data Resources Integration Resources aggregated 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

DDGrid Resources: 

DDGrid Resources DDGrid Apps. 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

DDGrid Resources: 

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.

Deployed commercial CDB (appr.700,000): 

Deployed commercial CDB (appr.700,000)

Slide24: 

appr. 3,300,000 compounds

CDB example：CNPD-China Natural Products Database: 

CDB example：CNPD-China Natural Products Database

CDB example：CNPD: 

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

CDB example：CNPD: 

CDB example：CNPD

CDB example：TCMD: 

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.

CDB example：TCMD: 

CDB example：TCMD

DDGrid applications in reality: 

DDGrid applications in reality SIMM carried out anti-SARS and anti-diabetes drug research using the DDGrid Anti-SARS drug research Anti-diabetes drug research

Slide31: 

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.x and PCT patent pi034248 Research on Anti-SARS medicine

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 Research on anti-diabetes medicine

Research on anti-diabetes medicine: 

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

New anti-diabetes drug: 

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

What does the DDGrid provide？: 

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

Collaboration: 

Collaboration Selected Users of DDGrid

DDGrid Demo: 

DDGrid Demo http://www.ddgrid.ac.cn Demo

Slide38: 

Demo

Slide39: 

Demo

Slide40: 

Demo

Slide41: 

Demo

Slide42: 

Demo

Thank you！: 

Thank you！ Q&A