Lecture 8 Bioinformatics of TCMLecture 8 Bioinformatics of TCM Y.Z. ChenY.Z. Chen
Department of PharmacyDepartment of PharmacyNational University of SingaporeNational University of Singapore
Tel: 65-6616-6877; Email: Tel: 65-6616-6877; Email: [email protected] ; Web: ; Web: http://bidd.nus.edu.sg
ContentContent• Overview of TCM Overview of TCM
• TCM and systems biologyTCM and systems biology
• Computer methods and databases of TCMComputer methods and databases of TCM
• Bioinformatics and TCMBioinformatics and TCM
TCM HistoryTCM 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.
TCM HistoryTCM 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 ).
TCM HistoryTCM 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 ).
TCM HistoryTCM 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).
TCM HistoryTCM 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.
Classification of TCM herbs based on Classification of TCM herbs based on traditional therapeutic classestraditional therapeutic classes
Classification of TCM herbs based on Classification of TCM herbs based on traditional therapeutic classestraditional therapeutic classes
Classification of TCM herbs based on Classification of TCM herbs based on traditional therapeutic classestraditional therapeutic classes
Classification of TCM herbs in traditional therapeutic classesClassification of TCM herbs in traditional therapeutic classes
Classification of TCM herbs based on Classification of TCM herbs based on traditional therapeutic classestraditional therapeutic classes
TCM TherapeuticsTCM Therapeutics
Potentially novel therapeutic approaches
Existing markets in certain countries and potential market in others
Pharmacology & Therapeutics 2000, 86:191-198
TCM TherapeuticsTCM 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
TCM TherapeuticsTCM 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
TCM TherapeuticsTCM Therapeutics
Multiple targets: therapeutic effects symptom treatment toxicity modulation Immune regulation drug delivery energy metabolism harmonization
Pharmacology & Therapeutics 2000, 86:191-198
TCM TherapeuticsTCM Therapeutics
TCM TherapeuticsTCM Therapeutics
Systems: the way for TCM to Systems: the way for TCM to produce clinical effectsproduce clinical effects
• Fact1: Weak effect of components• Fact2: Validated effect of TCM by clinical practice• Inference: Interaction among components
Direct Interaction(seldom)
Indirect Interaction
(often)
TCM relatedBiological system
• Systems are the targets of TCM function
TCM function
Targeting systems: interpreting the Targeting systems: interpreting the mechanism of TCM functionmechanism of TCM function
Direct Interaction(seldom)
Indirect Interaction(often)
TCM relatedBiological system
Mechanism of TCM function
Targeting systems: bridging biology Targeting systems: bridging biology and TCM theoryand TCM theory
Direct Interaction(seldom)
Indirect Interaction(often)
TCM relatedBiological system
TCM function
TCM theory
Targeting systems: providing new cues for the treatment of complex disease
Direct Interaction(seldom)
Indirect Interaction(often)
TCM relatedBiological system
TCM function
TCM theory Validated clinical prescription
Targeting systems: providing new resource for drug development
Direct Interaction(seldom)
Indirect Interaction(often)
TCM relatedBiological system
TCM function
TCM theory Validated clinical prescription
• Impact based molecular target selection• “Remote” interruption of systems• Complex drugs
A Proposed Platform for System-A Proposed Platform for System-targeting TCM researchtargeting TCM research
Database
TCM pathway
moltargets
Activecompnts
biosystems
Biological Systems related with TCM Biological Systems related with TCM Prescriptions that Promoting Blood Prescriptions that Promoting Blood
Circulation and Removing Blood StasisCirculation and Removing Blood Stasis
Map00590:prostaglandin and leukotriene metabolism
Map00230: purine metablism
Map00100: biosynthesis of steroids
Map00531: glycosaminoglycan degradation
Map00010: glycolysis/gluconeogenesis
Gaëlle Hardy, et. al.Urinary leukotriene E4 excretion is increased in type 1 diabetic patientsA 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
Biological Systems related with TCM Prescriptions that Biological Systems related with TCM Prescriptions that Promoting Blood Circulation and Removing Blood StasisPromoting Blood Circulation and Removing Blood Stasis
Computer Analysis of Molecular Computer Analysis of Molecular Mechanism of TCMMechanism of TCM
Y.Z. Chen and D.G. ZhiProteins 2001;43: 217
Traditional Medicine Database
Herbal Ingredient& ContentDatabase
TherapeuticTarget
Database
Drug AdverseReaction
Target Database
Drug AbsorptionDistributionMetabolismExcretion
Database
ComputerMatch-Making
Software
HerbalIngredient
Therapeutic Target
Toxicity Target
ADME protein
Collective therapeutic and maintenance effects Toxicity / side effects and modulation
Drug delivery and clearance
Matched Targets
Mutual Enhancement ?Mutual Counteraction ?
Maintenance or Balance ?Delivery or Clearance ?
Medicinal Herb Databases at BIDDMedicinal 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 Formula
Herb
Herb
Compound
Compound
Compound
Compound
Protein
Protein
Protein
Protein
Protein
Protein
Protein
Protein
Protein
Protein
Function
Function
Function
Function
Function
Function
Function
Structure
Structure
Structure
Structure
TCMD
TCHF Library
CNPD
TCSH Library
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
What bioinformatics can do in TCMWhat bioinformatics can do in TCM
1R4L from PDB
Pathway form KEGG
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
.Design of HIV-1 Protease Inhibitor
.Design of HIV-1 Protease Inhibitor
.Design of HIV-1 Protease Inhibitor
.Design of HIV-1 Protease Inhibitor
Scoring in Ligand-Protein Docking
Potential Energy Description:
D A H AH A/D AH/H E
ACE 177981 88 6563 52 5E-
04 0.79 16.02
AngII 177981 532 49172 490 0.00
3 1.00 3.33
PDE4 177981 285 31297 168 0.00
2 0.54 3.35
5-HT3 177981 278 40722 200 0.00
2 0.49 3.14
HMG-CoA
177981 215 33718 136 0.00
1 0.40 3.34D ： number of molecules in database
A ： number of active molecules in database
H ： number of hit molecules
AH ： number of active molecules in hitlistDAHAHE
//
Virtual ScreeningVirtual Screening
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INVDOCK Strategy for Match MakingINVDOCK Strategy for Match MakingExisting M ethods:
G iven a Protein,F ind Puta tive B inding L iga nds
From a C hem ica l D a ta base
Successful ly D ocke d C om poundsas Puta tive L igands
Protein
C om pound D a ta ba seC om pound 1
...C om pound n
N ew M ethod:G iven a L iga nd,
Find Puta tive Protein T a rgetsFrom a Protein D a ta ba se
S ucce ss fully D ocke d Prote insas Puta tive T arge ts
Liga nd
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Science 1992;257: 1078 Proteins 1999; 36:1
INVDOCK Test on INVDOCK Test on Targets of Chinese Medicinal Herbal Ingredients
(Am. J. Chin. Med. 2002, 30, 139)
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 TCM Target PredictionINVDOCK Test on TCM Target Prediction Therapeutic targets of Camptothecine (Am. J. Chin. Med. 2002, 30, 139)
PDB Protein Experimental Finding Target Status
Theraputic Effect Ref
1ads Aldose Reductase
Diabetes treatment
2gss Glutathione S-Transferase p1-1
Increases intracellular glutathione
Implicated Enhance radical scavenging activities that may useful in cancer treatment
Matsumoto
7ice DNA Polymerase Beta
Anti-cancer
1a25 Protein Kinase C Inhibitor Confirmed Induction of apoptosis in tumor.
Martelli Nieve-Neira
1cdk CAMP-Dependent Protein Kinase
Anti-cancer
3bct Beta-Catenin Induces apoptosis in leukemic cells.
1dvi Calpain Inhibition of calpain activities. Anti-cancer Eymin
1yfo Receptor Protein Tyrosine Phosphatase
Causes elevation of PTPase in the cytosol and the nucleus which play a critical role in the induction of the differentiation of IW32 erythroleukemia cells.
Anti-cancer Wang M
1a35 Topoisomerase I Inhibitor Wang MC
INVDOCK Test on TCM Target PredictionINVDOCK Test on TCM Target Prediction
Toxicity and side effect targets of Camptothecine (Am. J. Chin. Med. 2002, 30, 139)
PDB Protein Experimental Finding
TargetStatus
Toxicity/SideEffect
Ref.
2clj Acetylcholinesterase Reversible inhibition
Confirmed Causes Cholinergic Toxicity Dodds
1aqb Retinol-Binding Protein
Interfering with retinol transport that may cause complication in cancer and cardiovascular disease
5rla Arginase Increase blood urea level
Implicated
Hyperammonemia that may cause nerve toxicity
Yu ZJ
Network Regulation by Anticancer TCMNetwork Regulation by Anticancer TCM
Anticancer Effect of 贯叶连翘 St.John's WortDrug Discov Today 2009, 14, 579
Hypericin
Hypericin
HyperforinHyperforin
Cancer Counteraction
Cancer Counteraction
Synergistic Network Regulation by Herbal ProductSynergistic Network Regulation by Herbal Product
Synergistic Anti-HIV effect of Rosa damascena 突厥蔷薇Drug Discov Today 2009, 14, 579AIDS-058145: 2-Phenylethanol-O-(6-O-galloyl)-beta-D-glucopyranoside 8
Chinese Medicinal HerbsAll Other Herbs
All ingredients of the other herbs
Interior Warming Herbs
All ingredients of interior warming herbs
Exclusive ingredientsExclusive ingredients
COMPARE
Bioinformatics Study of Mechanism of TCM HerbsBioinformatics Study of Mechanism of TCM HerbsInterior Warming Herbs as an ExampleInterior Warming Herbs as an Example
Pharmacological effects possibly linked to interior warming
Other Pharmacological and regulatory effects
Interior warming effects primarily come from these ingredients
Pharmacological Effects Pharmacological Effects Possibly Linked to Interior WarmingPossibly Linked to Interior Warming
Vasodilation and its Relation to Interior WarmingVasodilation and its Relation to Interior Warming
• Common mode of action (except Hua Jiao)– Inhibit Ca2+ influx
• Other Modes of actions– Increase NO – Increase cGMP– Activate TRPV1– Alpha-adrenoceptor
blockade
• 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
1Rang HP, Dale MM, Ritter JM, P.K. M. Pharmacology. 5th ed. Edinburgh ; New York: Churchill Livingstone, 2003
Pharmacological Effects Pharmacological Effects Possibly Linked to Interior WarmingPossibly Linked to Interior Warming
TRPV1 Agonism and its Relation to Interior WarmingTRPV1 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
1Geppetti P, Materazzi S, Nicoletti P. Eur J Pharmacol 2006;533(1-3):207-14.
• 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 Associated with vasoconstrictionvasoconstriction
TRPV1 Agonism and its Relation to Interior WarmingTRPV1 Agonism and its Relation to Interior Warming• Dual actions leading to the
same warming effect or sensation?
1. 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
1Eldershaw T, Colquhoun E, Bennett K et al.
Life Sci 1994;55(5):389-97.
Vasodilation Thermogenesis
Bi Ba Bisabolene Piperine (Abolished by Bisabolene?)
Gan Jiang
10-gingerol(Net-effect?)
EffectEffect
HerbHerb
6-shogaol6-shogaol6-gingerol6-gingerol
6-shogaol6-shogaol6-gingerol6-gingerol
2. TRPV1 agonists reported to result in hypothermia due to response to thermogenesis and activation of warm sensors1,
– False sense of warmth– Not truly ‘therapeutic’
AcknowledgementAcknowledgementCurrent 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)
