Dr. Zhiwei Cao College of life science and biotechnology, Tongji University; Shanghai Center for Bioinformation Technology Computational Platform for Mechanistic Study of Chinese Herb

Overview 1.Introduction of Mechanistic Study of Chinese Herb 2.Computational Platform: Resources and Technologies 3.Case Study 4.Ongoing and future development

1. Introduction: Mechanism of Herbs Multiple Ingredients, Multiple Targets, Network Pharmacology & Therapeutics 2000, 86:

Questions about Herb Mechanism  What ingredients are active compounds?  What are their potential targets?  What are their targeted pathways?  How can we analyze the network?  …..

2. Platform: Resources and Technologies 1. China patent filed:  Identification of main active ingredients of herbs based on database technology (SCBIT) 2. US patent obtained:  INVDOCK to identify potential drug targets (BIDD) 3. Software license obtained:  Human intergrated PPI database (SCBIT) 4. China patent filed:  Computational platform and methodologies to support herbal mechanistic study (SCBIT)

2.1 Herbal Ingredient and Content database （ HICD)  Above 30 related journals ;  >3200 literatures being curated;  Herbs from 39 countries;  >15,000 ingredient with Content information;  Including all potential factors affecting ingredient content  Collecting time, site  herbal part…  Processing methods  Method to measure the content  Therapeutic effects  Diseases…

2.2. Computational Method to Identify Potential Targets (INVDOCK)  US patent authorized: 6,519,611 B1 (Feb )  German Merck testing in 2006  Getting improved both in BIDD and SCBIT  Getting Co-developed with Bridgeway high-computing company ( in Oct, 2007www.bridgeway.com.cn

2.3 Target network construction based on （ ISHIP ） 1. Experimental and predicted PPI > 610,000 pairs ； 2. > 29,000 with experimental evidence ； 3. Covering whole human genome, with confidence scoring system ； 4. Linking to genetic disease database (OMIM ）； 5. Software licensed: 2006SR05464 。

1.3 Integrated Source of Human interacting proteins （ ISHIP ）

Supporting various queries  支持多种检索方式  Protein accession  Gene symbol  GeneID  IPI accession  Keyword  BLAST Gene symbol search

2.4 Network analysis: System biology Pajek PIN bioverse

Network Decomposition Technology Complex networks theory for analyzing metabolic networks Chinese Science Bulletin 2006 vol. 51 No. 13 ，

E.Coli 代谢网络 12 个功能模块的 GSC 部分的连接图. 此图的每个强连通子图对应一个蝴蝶结结构 Zhao J, …, Cao ZW, Li YX. Hierarchical modularity of nested bow-ties in metabolic networks. BMC Bioinformatics Aug 18;7:386.

E.Coli 代谢网络的 12 个子网络之间的关系. 每个子网络具有相对独立的功能, 是生物学功能模块

Identifying topological modules and their functions Modular co-evolution of metabolic networks. BMC Bioinformatics 2007 ， 8:311.

3. Case study: ganoderic acid D  Main ingredient of tri-terpenoids in Ganoderma lucidum ( 灵芝）.  Inhibit hela cell proliferation  apoptosis  Target: 2-DE: 21 proteins  Question: what’s the target & pathway?

Minimization :21 proteins ( steiner) Proteomic characterization of the cytotoxic mechanism of ganoderic acid D and computer automated estimation of the possible drug-target network Molecular Cell Proteomics ：

4. Future development  Improvement of target-searching technology ( with BIDD, NUS)  Clustering and similarity search of active ingredients (with BIDD and Tongji)  Herbal toxicity study ( with Shanghai TCM university)  Formula validation…. ( with ….? )

Collaborative Opportunities  Experts on Chinese Herb  Experts on computational chemistry and physics  Experts on biologists  …

Acknowledgements  Funding from Shanghai Commission of Science and Technology  863 funding from China Ministry of Science and Technology  Prof. Chen yuzong BIDD group, NUS  Prof. Li Yixue, SCBIT  Shanghai TCM Modernizations Center “Whether from the East or the West, we share the same goal of improving human health.”

“If there is any technology that could lead to a breakthrough in traditional Chinese medicine, it will be systems biology,” – NATURE|Vol 448|12 July 2007