Transcript Essential Bioinformatics and Biocomputing (LSM2104

Lecture 8 Bioinformatics of TCM
Y.Z. Chen
Department of Pharmacy
National University of Singapore
Tel: 65-6616-6877; Email: [email protected] ; Web: http://bidd.nus.edu.sg
Content
• Overview of TCM
• TCM and systems biology
• Computer methods and databases of TCM
• Bioinformatics and TCM
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.
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).
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).
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).
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.
Classification of TCM herbs based on
traditional therapeutic classes
Classification of TCM herbs based on
traditional therapeutic classes
Classification of TCM herbs based on
traditional therapeutic classes
Classification of TCM herbs in traditional therapeutic classes
Classification of TCM herbs based on
traditional therapeutic classes
TCM Therapeutics
 Potentially novel
therapeutic
approaches
 Existing markets
in certain
countries and
potential market
in others
Pharmacology & Therapeutics 2000, 86:191-198
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
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
TCM Therapeutics
 Multiple targets:
 therapeutic effects
 symptom treatment
 toxicity modulation
 Immune regulation
 drug delivery
 energy metabolism
 harmonization
Pharmacology & Therapeutics
2000, 86:191-198
TCM Therapeutics
TCM Therapeutics
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
Direct
Interaction
(seldom)
Indirect
Interaction
(often)
TCM function
• Systems are the targets of TCM function
TCM related
Biological
system
Targeting systems: interpreting the
mechanism of TCM function
Indirect Interaction
Direct Interaction
(often)
(seldom)
TCM related
Biological system
Mechanism of TCM function
Targeting systems: bridging biology
and TCM theory
Indirect Interaction
Direct Interaction
(often)
(seldom)
TCM function
TCM theory
TCM related
Biological system
Targeting systems: providing new cues
for the treatment of complex disease
Indirect Interaction
Direct Interaction
(often)
(seldom)
TCM related
Biological system
TCM function
TCM theory Validated clinical prescription
Targeting systems: providing new
resource for drug development
• Impact
based molecular target selection
• “Remote” interruption of systems
• Complex drugs
Indirect Interaction
Direct Interaction
(often)
(seldom)
TCM related
Biological system
TCM function
TCM theory Validated clinical prescription
A Proposed Platform for Systemtargeting TCM research
TCM
pathway
Database
Active
compnts
mol
targets
bio
systems
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
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
Computer Analysis of Molecular
Mechanism of TCM
Therapeutic Target
Traditional
Medicine
Database

Herbal
Ingredient
Computer
Match-Making
Software

Toxicity Target
ADME protein
Herbal
Ingredient
& Content
Database

Matched Targets
Mutual Enhancement ?
Mutual Counteraction ?
Maintenance or Balance ?
Delivery or Clearance ?
Therapeutic
Target
Database 
Drug Adverse
Reaction
Target
Database 
Drug Absorption
Distribution
Metabolism
Excretion
Database 
 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
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
Comparison with
existing TCM
databases:
Formula:
Function
TCM-ID: 1000
TCHFL: 270
Herb:
TCM Formula
TCM-ID: 1200
TCSHL: 520
TCMD: 1500
Compound:
TCHF Library
TCM-ID: 9000
CNPD: 3000
TCSH Library
TCMD: 6800
Function
Structure
Protein
Protein
Compound
Protein
Herb
Function
Structure
Protein
Compound
Function
Protein
Structure
Function
Protein
Protein
Compound
Protein
Herb
Function
Compound
TCMD
CNPD
Structure
Protein
Protein
What 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:
Virtual Screening
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
0.003
1.00
3.33
PDE4
177981
285
31297
168
0.002
0.54
3.35
5-HT3
177981
278
40722
200
0.002
0.49
3.14
HMG-CoA
177981
215
33718
136
0.001
0.40
3.34
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
AH / H
E
A/ D
¸Î ϸ °û
ÃâÒß
´Ì ¼¤
OH
OH
HMG
-CoA
HMG
-CoA
OH
HO
H H
HO
OH
HO
µ¨¹Ì
´¼
OH
OH
HO
OH
HO
O
OH
H COO-
HO
O
OH
O
O
O
Tϸ °ûÃâÒß
Ïì Ó¦
T-cell
TNFɑ
×éÖ¯
ËðÉË
OH
O
O
COO-
OH
O
O
O
O
O
HO
HO
O
H3C
OH
HO
O
OH
HO
HO
O
O
HO
O
O
O
H
OH
OH
H
O
3
Ѫ¹Ü
HC
°ß¿é OH
HO
O
O
HO
OH
OH
H H
OH
O
HO
H
HO
O
O
OH
O
HO
O HC
3
H
HO
COO-
O
O
O
OH
CH3
HO
OH
CH3
HO
O
H3C
O
CH3
H
O
O
O
CH3
O
O
OH
OH
COX
2
COX2
CH3
PGE
2
H3C
OH
CH×éÖ¯
3
ËðOÉË
O
O
CH3
H3C
PDE
GM
P
OH
CH3
CH3
H3C
O
CH3
O
OH
O
O
HO
O
OH
µ°°×¼¤
øG
PIP2
/ IP3
HO
ACE
H
CH3
AngII
Ca
Àë×Ó
ƽ
»¬¼¡Ï¸ °û
HO
O
H H
H
O
Mg
COOO
OH CO
O
O
HO
OH
O
H
OH
O
2+
HO
OO
H
OH
OH
O H
HO
OH
HO
HO
OH
OH
HO
O
OH
OH
CH 3
O
HO
O
HO
O
HO
HO
HO
Ang
II
OH
O
O
O
Ang
II R
Ѫ¹ÜÊÕ
Ëõ£¬Ñª
ѹÉý¸ß
OH
O
HO
O
O
OH
O
CH3
O
HO
OH
H 3C
OH
H3C
OH
OH
O
O
OH
O
O
O
OH
O
O
O
ÖÐ
ÊàÉñOH
¾-ÔªÃô
¸ÐÐÔ
O
PDE
O
HO
HO
O
O
HO
CH3
3
O
CH3
H3C
OH
HO
O Éñ
ÖÜ
±ß
CH
¾-ÔªÃô
¸ÐÐÔ
OH
HO
HO
O
CH3
HO
OH
O
CH3
CH3
H
O
CH3
O
O
O
H
OH
CH3
O
O
OH
CH3
CH3
HO
O
HO
TNF
R
CH3
H COOCH3
O
H3C
O
H 3C
HO
H3C
HO
OH
O
OH OH
OH
O
CH3
OH
O
O
CH3
PGE
/ EP
CH3
CH3
CH3
OH
O
O
O
O
O
O
O
O
O
Mg
CH3
CH3
O
2+
H
O
O
CH3
OH
CH3
HO
O
HO
OH
O
O
OH
OH
OH
OH
O
CH3
3
C
C
C
H3
C
H3
CH
H
CH3
OH
H 3C
H3
OH
H3
CH3
ÅÝHÄϸ
°û
O
HO
CH3
HO
HO
O
OH
3
O
O
O
O
H3C
O
3
O
O
CH3
O
OH
O
OH
O
Ѫ¹ÜÐÂ
O
HC
Éú
Òò×ÓCH
TNF
R
OH
HO
OH
O
O
LDLOH
O
O
O
TNFa
OH
O
ÄÚ
Ƥ
ϸ O
°ûÔöÖ³
C
CH3H 3
CH3
O
O
OH
O
O
CH 2
O
OH
OH
O
HO
OH
O
HO
O
CH 3
O
O
CH3
O
O
O
ÄÚ
Ƥ
ϸ °û
OH
O
CH3
O
OH
O
O
CH 3
O
¾Þ
ÊÉϸ °û
O
OH
2+
H
Mg
O
O
HO
HO
OH
O
HO
O
O
OH
OH
OH
INVDOCK Strategy for Match Making
Existing Methods:
New Method:
Given a Protein,
Find Putative Binding Ligands
From a Chemical Database
Given a Ligand,
Find Putative Protein Targets
From a Protein Database
Compound Database
Protein Database
Compound 1
...
Compound n
Protein 1
...
Protein n
Protein
Ligand
Successfully Docked Compounds
as Putative Ligands
Successfully Docked Proteins
as Putative Targets
Science 1992;257: 1078
Proteins 1999; 36:1
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 Prediction
Therapeutic targets of Camptothecine (Am. J. Chin. Med. 2002, 30, 139)
PDB
Protein
Experimental Finding
Target
Status
Theraputic Effect
Ref
1ads
Aldose
Reductase
2gss
Glutathione STransferase p1-1
7ice
DNA Polymerase
Beta
1a25
Protein Kinase C
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
Diabetes treatment
Increases intracellular
glutathione
Implicated
Enhance radical
scavenging activities that
may useful in cancer
treatment
Matsumoto
Anti-cancer
Inhibitor
Confirmed
Induction of apoptosis in
tumor.
Martelli Nieve-Neira
Wang MC
INVDOCK Test on TCM Target Prediction
Toxicity and side effect targets of Camptothecine
(Am. J. Chin. Med. 2002, 30, 139)
PDB
Protein
Experimental
Finding
2clj
Acetylcholinesterase
Reversible
inhibition
1aqb
Retinol-Binding
Protein
5rla
Arginase
Target
Status
Confirmed
Toxicity/Side
Effect
Causes Cholinergic Toxicity
Ref.
Dodds
Interfering with retinol transport that
may cause complication in cancer and
cardiovascular disease
Increase blood
urea level
Implicate
d
Hyperammonemia that may cause
nerve toxicity
Yu ZJ
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
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
Bioinformatics Study of Mechanism of TCM Herbs
Interior Warming Herbs as an Example
Chinese Medicinal Herbs
Interior Warming Herbs
All ingredients of
interior warming herbs
Interior warming
effects primarily come
from these ingredients
All Other Herbs
All ingredients of
the other herbs
COMPARE
Exclusive ingredients
Pharmacological effects possibly
linked to interior warming
Other Pharmacological
and regulatory effects
Pharmacological Effects
Possibly Linked to Interior Warming
Vasodilation 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
1Rang
• 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
HP, Dale MM, Ritter JM, P.K. M. Pharmacology. 5th ed. Edinburgh ; New York:
Churchill Livingstone, 2003
Pharmacological Effects
Possibly Linked to Interior Warming
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.
TRPV1 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.
Effect Vasodilation Thermogenesis
Herb
Bi Ba
Gan
Jiang
Bisabolene
Piperine
(Abolished by
Bisabolene?)
6-shogaol
6-gingerol
6-shogaol
6-gingerol
10-gingerol
(Net-effect?)
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’
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)