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Content Overview of TCM TCM and systems biology Computer methods and databases of TCM

Lecture 8 Bioinformatics of TCM Y.Z. Chen Department of Pharmacy National University of Singapore Tel: 65-6616-6877; Email: phacyz@nus.edu.sg ; Web: http://bidd.nus.edu.sg. Content Overview of TCM TCM and systems biology Computer methods and databases of TCM Bioinformatics and TCM.

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Content Overview of TCM TCM and systems biology Computer methods and databases of TCM

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  1. Lecture 8 Bioinformatics of TCMY.Z. ChenDepartment of PharmacyNational University of SingaporeTel: 65-6616-6877; Email: phacyz@nus.edu.sg ; Web: http://bidd.nus.edu.sg • Content • Overview of TCM • TCM and systems biology • Computer methods and databases of TCM • Bioinformatics and TCM

  2. TCM History • The history of TCM can be summarized by a list of important doctors and books. • Unknown, Huángdì nèijīng (黃帝內經/黄帝内经) (Yellow Emperor's Inner Canon) - Sùwèn (素问/素問) and Língshū (灵枢/靈樞). The earliest classic of TCM passed on to the present. • Warring States Period (5th century BC to 221 BC): Silk manuscripts recording channels and collaterals, Zubi shiyi mai jiu jing (足臂十一脉灸经/足臂十一脈灸經) (Moxibustion Classic of the Eleven Channels of Legs and Arms), and Yinyang shiyi mai jiu jing (阴阳十一脉灸经/陰陽十一脈灸經) (Moxibustion Classic on the Eleven Yin and Yang Channels). The latter was part of a cache of texts found in Mawangdui in the 1970s.

  3. TCM History Han Dynasty (206 BC–AD 220) to Three Kingdoms Period (220 - 280 AD): Zhenjiu zhenzhong jing (针灸枕中经/鍼灸枕中經) (Classic of Moxibustion and Acupuncture Preserved in a Pillow) by Huà Tuó (华佗/華佗). Shanghan zabing lun (伤寒杂病论/傷寒雜病論), which has since been split into two texts: the Shānghán lùn (伤寒论/傷寒論) ("Treatise on Cold Damage [Disorders]" - focusing on febrile conditions attributed to "Cold") and the Jingui yaolue (金匱要略) ("Essentials of the Golden Cabinet" - focusing on "miscellaneous illnesses") by Zhāng Zhòngjǐng (张仲景/張仲景). Jìn Dynasty (265-420): Zhēnjiǔ jiǎyǐ jīng (针灸甲乙经/鍼灸甲乙經) (Systematic Classic of Acupuncture and Moxibustion) by Huángfǔ Mì (皇甫谧/皇甫謐).

  4. TCM History Tang Dynasty (618–907) Beiji qianjin yaofang (备急千金要方/備急千金要方) (Emergency Formulas Worth a Thousand in Gold) and Qianjin yifang (千金翼方) (Supplement to the Formulas Worth a Thousand in Gold) by Sūn Sīmiǎo (孙思邈/孫思邈). Waitai miyao (外台秘要/外臺秘要) (Arcane Essentials from the Imperial Library) by Wang Tao (王焘/王燾). Song Dynasty (960 – 1279): Tóngrén shūxué zhēnjiǔ tújīng (铜人腧穴针灸图经/銅人腧穴鍼灸圖經) (Illustrated Manual of the Practice of Acupuncture and Moxibustion at (the Transmission) (and other) Acu-points, for use with the Bronze Figure) by Wáng Wéiyī (王惟一). Yuan Dynasty (1271 to 1368): Shísì jīng fāhuī (十四经发挥/十四經發揮) (Exposition of the Fourteen Channels) by Huá Shòu (滑寿/滑壽).

  5. TCM History Ming Dynasty (1368 to 1644): golden age of acupuncture and moxibustion. Many famous doctors and books. To name only a few: Zhēnjiǔ dàquan (针灸大全/鍼灸大全) (A Complete Collection of Acupuncture and Moxibustion) by Xu Feng (徐凤/徐鳳). Zhēnjiǔ jùyīng fāhuī (针灸聚英发挥/鍼灸聚英發揮) (An Exemplary Collection of Acupuncture and Moxibustion and their Essentials) by Gāo Wǔ (高武). Zhēnjiǔ dàchéng (针灸大成/鍼灸大成) (Compendium of Acupuncture and Moxibustion) by Yáng Jìzhōu (杨继洲/楊繼洲), completed in 1601. Běncǎo gāngmù (本草纲目/本草綱目) (Compendium of Materia Medica) by Lǐ Shízhēn (李时珍/李時珍), the most complete and comprehensive pre-modern herbal book (completed in 1578). Wenyi lun (温疫论/溫疫論), by Wu Youxing 吴有性 (1642).

  6. TCM History Qing Dynasty (1644-1912): Yizong jinjian (医宗金鉴/醫宗金鑒) (Golden Mirror of the Medical Tradition) compiled by Wu Qian (吴谦/吴謙) under imperial commission. Zhenjiu fengyuan (针灸逢源/鍼灸逢源) (The Source of Acupuncture and Moxibustion) by Li Xuechuan (李学川/李學川). Wenre lun (温热论/溫熱論), by Ye Tianshi (叶天士/業天士). Wenbing tiaobian (温病条辨/溫病條辨) (Systematized Identification of Warm-factor disorders) compiled by Wu Jutong (吴鞠通) in 1798.

  7. Classification of TCM herbs based on traditional therapeutic classes

  8. Classification of TCM herbs based on traditional therapeutic classes

  9. Classification of TCM herbs based on traditional therapeutic classes

  10. Classification of TCM herbs in traditional therapeutic classes

  11. Classification of TCM herbs based on traditional therapeutic classes

  12. TCM Therapeutics Potentially novel therapeutic approaches Existing markets in certain countries and potential market in others Pharmacology & Therapeutics 2000, 86:191-198

  13. TCM Therapeutics Need for standardization, validation, & further development Markers for standardization Molecular mechanism Safety and efficacy tests New recipes, combination drug mimics Pharmacology & Therapeutics 2000, 86:191-198

  14. TCM Therapeutics • Multiple herb therapies • Collective synergistic actions, maintenance and balance. • Mutual accentuation mutual enhancement mutual counteraction mutual suppression mutual antagonism mutual incompatibility Pharmacology & Therapeutics 2000, 86:191-198

  15. TCM Therapeutics • Multiple targets: • therapeutic effects • symptom treatment • toxicity modulation • Immune regulation • drug delivery • energy metabolism • harmonization Pharmacology & Therapeutics 2000, 86:191-198

  16. TCM Therapeutics

  17. TCM Therapeutics

  18. Systems: the way for TCM to produce clinical effects • Fact1: Weak effect of components • Fact2: Validated effect of TCM by clinical practice • Inference: Interaction among components Indirect Interaction (often) TCM related Biological system Direct Interaction (seldom) TCM function • Systems are the targets of TCM function

  19. Targeting systems: interpreting the mechanism of TCM function Indirect Interaction (often) TCM related Biological system Direct Interaction (seldom) Mechanism of TCM function

  20. Targeting systems: bridging biology and TCM theory Indirect Interaction (often) TCM related Biological system Direct Interaction (seldom) TCM function TCM theory

  21. Targeting systems: providing new cues for the treatment of complex disease Indirect Interaction (often) TCM related Biological system Direct Interaction (seldom) TCM function TCM theory Validated clinical prescription

  22. Targeting systems: providing new resource for drug development • Impact based molecular target selection • “Remote” interruption of systems • Complex drugs Indirect Interaction (often) TCM related Biological system Direct Interaction (seldom) TCM function TCM theory Validated clinical prescription

  23. A Proposed Platform for System-targeting TCM research pathway TCM Database Active compnts bio systems mol targets

  24. Biological Systems related with TCM Prescriptions that Promoting Blood Circulation and Removing Blood Stasis Map00100: biosynthesis of steroids Map00010: glycolysis /gluconeogenesis Map00230: purine metablism Map00590:prostaglandin and leukotriene metabolism Map00531: glycosaminoglycan degradation

  25. Biological Systems related with TCM Prescriptions that Promoting Blood Circulation and Removing Blood Stasis Gaëlle Hardy, et. al. Urinary leukotriene E4 excretion is increased in type 1 diabetic patients A quantification by liquid chromatography–tandem mass spectrometry. Prostaglandins Other Lipid Mediat.2005. 78(1-4):291-299 220 paper’s title in中国期刊网CNKI containing: promoting blood circulation and removing blood stasis + diabetes

  26. Computer Analysis of Molecular Mechanism of TCM Therapeutic Target Therapeutic Target Database Herbal Ingredient Computer Match-Making Software  Traditional Medicine Database  Toxicity Target Drug Adverse Reaction Target Database  ADME protein Matched Targets Herbal Ingredient & Content Database  Drug Absorption Distribution Metabolism Excretion Database  Mutual Enhancement ? Mutual Counteraction ? Maintenance or Balance ? Delivery or Clearance ? • Collective therapeutic and maintenance effects • Toxicity / side effects and modulation • Drug delivery and clearance Y.Z. Chen and D.G. Zhi Proteins 2001;43: 217

  27. Medicinal Herb Databases at BIDD • TCM-ID: Traditional Chinese Medicine -Information Database  • Only database providing integrated and comprehensive info about: • TCM formula, constituent herbs, herbal ingredients, effect on proteins • Molecular structure • Function at the formula, herb and compound levels Function Structure Protein • Comparison with • existing TCM • databases: • Formula: • TCM-ID: 1000 • TCHFL: 270 • Herb: • TCM-ID: 1200 • TCSHL: 520 • TCMD: 1500 • Compound: • TCM-ID: 9000 • CNPD: 3000 • TCMD: 6800 Protein Compound Function Protein Herb Function Structure Protein Function Compound Protein Function Structure Protein TCM Formula Function Protein Compound Protein Herb TCHF Library Structure Function Protein Protein Compound TCSH Library TCMD CNPD

  28. What bioinformatics can do in TCM 1R4L  from PDB Pathway form KEGG

  29. General Protein–Ligand Binding • Ligand - Molecule that binds with a protein - DNA, drug lead compounds, etc. • Protein active site(s) - Allosteric binding - Competitive binding • Function of binding interaction - Natural and artificial

  30. . Design of HIV-1 Protease Inhibitor

  31. . Design of HIV-1 Protease Inhibitor

  32. . Design of HIV-1 Protease Inhibitor

  33. . Design of HIV-1 Protease Inhibitor

  34. Scoring in Ligand-Protein Docking Potential Energy Description:

  35. Virtual Screening D：number of molecules in database A：number of active molecules in database H：number of hit molecules AH：number of active molecules in hitlist

  36. HMG -CoA T-cell TNFɑ COX2 PDE AngII

  37. INVDOCK Strategy for Match Making Science 1992;257: 1078 Proteins 1999; 36:1

  38. Chinese Natural Product Number of Identified Putative and Known Therapeutic Targets Number Confirmed or Implicated Therapeutic Targets by experiment Number of Identified Putative and Known Toxicity/Side effect Targets Number Confirmed or Implicated Toxicity/Side Effect Targets by experiment Acronycine 3 1 4 - Allicin 5 2 1 1 Baicalin 14 4 6 - Catechin 17 12 5 - Camptothecine 9 6 3 2 Dicoumarin 7 1 3 1 Emodin 6 3 5 1 Genistin 22 7 12 1 INVDOCK Test on Targets of Chinese Medicinal Herbal Ingredients(Am. J. Chin. Med. 2002, 30, 139)

  39. INVDOCK Test on TCM Target PredictionTherapeutic targets of Camptothecine(Am. J. Chin. Med. 2002, 30, 139)

  40. INVDOCK Test on TCM Target PredictionToxicity and side effect targets of Camptothecine(Am. J. Chin. Med. 2002, 30, 139)

  41. Network Regulation by Anticancer TCM Hyperforin Hyperforin Cancer Counteraction Cancer Counteraction Hypericin Hypericin Anticancer Effect of 贯叶连翘 St.John's Wort Drug Discov Today 2009, 14, 579

  42. Synergistic Network Regulation by Herbal Product Synergistic Anti-HIV effect of Rosa damascena 突厥蔷薇 Drug Discov Today 2009, 14, 579 AIDS-058145: 2-Phenylethanol-O-(6-O-galloyl)-beta-D-glucopyranoside 8

  43. Exclusive ingredients Bioinformatics Study of Mechanism of TCM HerbsInterior Warming Herbs as an Example Chinese Medicinal Herbs Interior Warming Herbs All Other Herbs All ingredients of interior warming herbs All ingredients of the other herbs Interior warming effects primarily come from these ingredients COMPARE Exclusive ingredients Pharmacological effects possibly linked to interior warming Other Pharmacological and regulatory effects

  44. Pharmacological Effects Possibly Linked to Interior Warming

  45. Vasodilation and its Relation to Interior Warming • Why vasodiation produces warming effect or sensation? • Blushing • A result of vasodilation • Warm feeling • Cold extremeties due to loss of beta-adrenoceptor mediated vasodilation • Increased lumen size of blood vessels • More blood brought to vasodilated area •  Warm sensation • Common mode of action (except Hua Jiao) • Inhibit Ca2+ influx • Other Modes of actions • Increase NO • Increase cGMP • Activate TRPV1 • Alpha-adrenoceptor blockade 1Rang HP, Dale MM, Ritter JM, P.K. M. Pharmacology. 5th ed. Edinburgh ; New York: Churchill Livingstone, 2003

  46. Pharmacological Effects Possibly Linked to Interior Warming

  47. TRPV1 Agonism and its Relation to Interior Warming • Transient receptor potential ion channel of vanilloid type 1 • Highly expressed in a subset of primary sensory neurons of the trigeminal, vagal and dorsal root ganglia • Non-neuronal cells1 • Activation leads to many effects • Burning sensation • Vasodilation • via release of Calcitonin gene related peptide (CGRP) • Inhibit gastric leisions • Thermogenesis • Piperine, 6-gingerol, 10-gingerol, 6-shogaol Associated with vasoconstriction 1Geppetti P, Materazzi S, Nicoletti P. Eur J Pharmacol 2006;533(1-3):207-14.

  48. TRPV1 Agonism and its Relation to Interior Warming Effect Herb • Dual actions leading to the same warming effect or sensation? • TRPV1 causes both vasodilation and vasoconstriction under different conditions1 • Directly induce vascular smooth muscle contraction, linked to thermogenesis that is abolished by vasodilators • But release neuropeptides e.g. CGRP that causes vasodilation 6-shogaol 6-gingerol 6-shogaol 6-gingerol • TRPV1 agonists reported to result in hypothermia due to response to thermogenesis and activation of warm sensors1, • False sense of warmth • Not truly ‘therapeutic’ 1Eldershaw T, Colquhoun E, Bennett K et al. Life Sci 1994;55(5):389-97.

  49. Acknowledgement • Current Group Members: • Computer-Aided Drug Design: CY Ung, XH Ma, XH Liu, Pankaj Kumar, F Zhu, X Liu, J Jia • Protein Function, Interaction, Network: HL Zhang, CY Ung, XH Ma, F Zhu, WK Teo, Z Shi • Databases and Servers: J Jia • Medicinal Herb: CY Ung, Pankaj Kumar, Cao Jinyi(undergraduate students) • Microarray and biomarkers: J Jia, ZQ Tang • Former Members: • PhD: • ZW Cao (Prof SCBIT, Tongji U), ZL Ji (Assoc Prof Xiamen U), X Chen (Assoc Prof Zhejiang U), • CW Yap (Assist Prof NUS), LY Han (Postdoc NIH), CJ Zheng (Postdoc NIH), • HH Lin (Postdoc Harvard ), J Cui (Postdoc U Georgia), H Li (Postdoc Einstein College Med) • Research Fellow/Assistant: • ZR Li (Assoc Prof SiChuan U), Y Xue (Prof SiChuan U), W Liu (Assoc Prof DUT), • D Mi (Assoc Prof DUT), CZ Cai (Prof ChongQing U), DG Zhi (Postdoc, Berkeley), • MSc: • Y.J. Guo (Postdoc NIH), L.Z. Sun (RA, U Tenn.), J. F. Wang (MSU), L.X. Yao (Columbia), • S Ong (Washington U), H Zhou (local company), B Xie (local company) • BSc: • W.K. Yeo (IMCB, Novartis)

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