Transcript Essential Bioinformatics and Biocomputing (LSM2104

Predicting Receptor targets of Traditional Chinese
Medicines and Small Molecule TCM Database
J. Jia and Y.Z. Chen
Department of Pharmacy
National University of Singapore
Tel: 65-6616-6877; Email: [email protected] ; Web: http://bidd.nus.edu.sg
Content
• TCM mechanism, targets, roles of bioinformatics and modeling
• TCM and target databases
• Target prediction by INVDOCK
• Bioinformatics study of mechanism of interior warming herbs
Therapeutics from Traditional Medicines

Potentially novel therapeutic
approaches

Existing markets in certain
countries and potential market
in others

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
Why receptor targets?
Therapeutics from Traditional Medicines


Multiple herb therapies
Collective synergistic
actions, maintenance and
balance.
 Mutual accentuation
mutual enhancement
mutual counteraction
mutual suppression
mutual antagonism
mutual incompatibility

Multiple targets:
 therapeutic effects
 symptom treatment
 toxicity modulation
 Immune regulation
 drug delivery
 energy metabolism
 harmonization
Pharmacology & Therapeutics
2000, 86:191-198
Computer Analysis of Molecular
Mechanism of Traditional Medicine
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
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
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)