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

Lecture 8 Bioinformatics of TCM

Y.Z. Chen Department of PharmacyNational University of Singapore Tel: 65-6616-6877; Email: [email protected] ; Web: http://bidd.nus.edu.sg

ContentOverview of TCM TCM and systems biologyComputer methods and databases of TCMBioinformatics and TCM

Essential Bioinformatics and Biocomputing (LSM2104)

TCM History

The history of TCM can be summarized by a list of important doctors and books.Unknown, Hungd nijng (/) (Yellow Emperor's Inner Canon) - Swn (/) and Lngsh (/). 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 (/) (Moxibustion Classic of the Eleven Channels of Legs and Arms), and Yinyang shiyi mai jiu jing (/) (Moxibustion Classic on the Eleven Yin and Yang Channels). The latter was part of a cache of texts found in Mawangdui in the 1970s.

TCM History

Han Dynasty (206 BCAD 220) to Three Kingdoms Period (220 - 280 AD): Zhenjiu zhenzhong jing (/) (Classic of Moxibustion and Acupuncture Preserved in a Pillow) by Hu Tu (/).Shanghan zabing lun (/), which has since been split into two texts: the Shnghn ln (/) ("Treatise on Cold Damage [Disorders]" - focusing on febrile conditions attributed to "Cold") and the Jingui yaolue () ("Essentials of the Golden Cabinet" - focusing on "miscellaneous illnesses") by Zhng Zhngjng (/).Jn Dynasty (265-420): Zhnji jiy jng (/) (Systematic Classic of Acupuncture and Moxibustion) by Hungf M (/).

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TCM History

Tang Dynasty (618907)Beiji qianjin yaofang (/) (Emergency Formulas Worth a Thousand in Gold) and Qianjin yifang () (Supplement to the Formulas Worth a Thousand in Gold) by Sn Smio (/).Waitai miyao (/) (Arcane Essentials from the Imperial Library) by Wang Tao (/).Song Dynasty (960 1279):Tngrn shxu zhnji tjng (/) (Illustrated Manual of the Practice of Acupuncture and Moxibustion at (the Transmission) (and other) Acu-points, for use with the Bronze Figure) by Wng Wiy ().Yuan Dynasty (1271 to 1368): Shs jng fhu (/) (Exposition of the Fourteen Channels) by Hu Shu (/).

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TCM History

Ming Dynasty (1368 to 1644): golden age of acupuncture and moxibustion. Many famous doctors and books. To name only a few:Zhnji dquan (/) (A Complete Collection of Acupuncture and Moxibustion) by Xu Feng (/).Zhnji jyng fhu (/) (An Exemplary Collection of Acupuncture and Moxibustion and their Essentials) by Go W ().Zhnji dchng (/) (Compendium of Acupuncture and Moxibustion) by Yng Jzhu (/), completed in 1601.Bnco gngm (/) (Compendium of Materia Medica) by L Shzhn (/), the most complete and comprehensive pre-modern herbal book (completed in 1578).Wenyi lun (/), by Wu Youxing (1642).

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TCM History

Qing Dynasty (1644-1912):Yizong jinjian (/) (Golden Mirror of the Medical Tradition) compiled by Wu Qian (/) under imperial commission.Zhenjiu fengyuan (/) (The Source of Acupuncture and Moxibustion) by Li Xuechuan (/).Wenre lun (/), by Ye Tianshi (/).Wenbing tiaobian (/) (Systematized Identification of Warm-factor disorders) compiled by Wu Jutong () in 1798.

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Classification of TCM herbs based on traditional therapeutic classes

Essential Bioinformatics and Biocomputing (LSM2104)

Classification of TCM herbs based on traditional therapeutic classes

Essential Bioinformatics and Biocomputing (LSM2104)

Classification of TCM herbs based on traditional therapeutic classes

Essential Bioinformatics and Biocomputing (LSM2104)

Classification of TCM herbs in traditional therapeutic classes

Essential Bioinformatics and Biocomputing (LSM2104)

Classification of TCM herbs based on traditional therapeutic classes

Essential Bioinformatics and Biocomputing (LSM2104)

TCM Therapeutics

Potentially novel therapeutic approachesExisting markets in certain countries and potential market in othersPharmacology & Therapeutics 2000, 86:191-198

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TCM Therapeutics

Need for standardization, validation, & further developmentMarkers for standardizationMolecular mechanismSafety and efficacy testsNew recipes, combination drug mimicsPharmacology & Therapeutics 2000, 86:191-198

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TCM Therapeutics

Multiple herb therapiesCollective synergistic actions, maintenance and balance.

Mutual accentuation mutual enhancement mutual counteraction mutual suppression mutual antagonism mutual incompatibility

Pharmacology & Therapeutics 2000, 86:191-198

TCM Therapeutics

Multiple targets: therapeutic effectssymptom treatmenttoxicity modulationImmune regulation drug delivery energy metabolismharmonizationPharmacology & Therapeutics 2000, 86:191-198

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TCM Therapeutics

Essential Bioinformatics and Biocomputing (LSM2104)

TCM Therapeutics

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Systems: the way for TCM to produce clinical effectsFact1: Weak effect of componentsFact2: Validated effect of TCM by clinical practiceInference: Interaction among componentsDirect Interaction(seldom)Indirect Interaction(often)TCM relatedBiological systemSystems are the targets of TCM function

TCM function

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Targeting systems: interpreting the mechanism of TCM functionDirect Interaction(seldom)Indirect Interaction(often)TCM relatedBiological systemMechanism of TCM function

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Targeting systems: bridging biology and TCM theoryDirect Interaction(seldom)Indirect Interaction(often)TCM relatedBiological systemTCM functionTCM theory

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Targeting systems: providing new cues for the treatment of complex diseaseDirect Interaction(seldom)Indirect Interaction(often)TCM relatedBiological systemTCM functionTCM theoryValidated clinical prescription

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Targeting systems: providing new resource for drug developmentDirect Interaction(seldom)Indirect Interaction(often)TCM relatedBiological systemTCM functionTCM theoryValidated clinical prescription Impact based molecular target selection Remote interruption of systems Complex drugs

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A Proposed Platform for System-targeting TCM researchDatabaseTCMpathwaymoltargetsActivecompntsbiosystems

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Biological Systems related with TCM Prescriptions that Promoting Blood Circulation and Removing Blood Stasis Map00590:prostaglandin and leukotriene metabolismMap00230: purine metablismMap00100: biosynthesis of steroidsMap00531: glycosaminoglycan degradationMap00010: glycolysis/gluconeogenesis

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Galle Hardy, et. al.Urinary leukotriene E4 excretion is increased in type 1 diabetic patientsA quantification by liquid chromatographytandem mass spectrometry.Prostaglandins Other Lipid Mediat. 2005. 78(1-4):291-299 220 papers title inCNKI containing:promoting blood circulation and removing blood stasis+ diabetesBiological Systems related with TCM Prescriptions that Promoting Blood Circulation and Removing Blood Stasis

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Computer Analysis of Molecular Mechanism of TCMY.Z. Chen and D.G. ZhiProteins 2001;43: 217 Traditional Medicine DatabaseHerbal Ingredient& ContentDatabase TherapeuticTarget Database Drug AdverseReactionTarget Database Drug AbsorptionDistributionMetabolismExcretion Database ComputerMatch-MakingSoftwareHerbalIngredientTherapeutic TargetToxicity TargetADME proteinCollective therapeutic and maintenance effectsToxicity / side effects and modulationDrug delivery and clearanceMatched TargetsMutual Enhancement ?Mutual Counteraction ?Maintenance or Balance ?Delivery or Clearance ?

Medicinal Herb Databases at BIDD

Comparison with existing TCM databases:

Formula: TCM-ID: 1000 TCHFL: 270Herb: TCM-ID: 1200 TCSHL: 520 TCMD: 1500Compound: TCM-ID: 9000 CNPD: 3000 TCMD: 6800

TCM FormulaHerbHerbCompoundCompoundCompoundCompoundProteinProteinProteinProteinProteinProteinProteinProteinProteinProteinFunctionFunctionFunctionFunctionFunctionFunctionFunctionStructureStructureStructureStructureTCMDTCHF LibraryCNPDTCSH LibraryTCM-ID: Traditional Chinese Medicine - Information Database

Only database providing integrated and comprehensive info about:TCM formula, constituent herbs, herbal ingredients, effect on proteinsMolecular structure Function at the formula, herb and compound levels

What bioinformatics can do in TCM1R4L from PDBPathway form KEGG

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General ProteinLigand BindingLigand- Molecule that binds with a protein- DNA, drug lead compounds, etc.Protein active site(s)- Allosteric binding- Competitive bindingFunction of binding interaction- Natural and artificial

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.Design of HIV-1 Protease Inhibitor

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.Design of HIV-1 Protease Inhibito