Transcript SINGAPORE’S R&D FRAMEWORK and the TECHNOLOGY DEVELOPMENT

Lecture 8: Drug Target Identification and
Mechanistic Study of Herbs
Y.Z Chen
Dept. of Comptational Science
National University of Singapore
 Why mechanism of herbs?
 Why computer approach?
 How it works?
 Performance Analysis and
future plan
Herbal Medicine and Society
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Widely used in Asian (China, India, Japan, Korea, Singapore etc. ) and other
nations (120 nations established relevant organizations and facilities, as reported by XinHua
news agency in 24/2/2000).
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Increased popularity in western countries (12% of the population in USA
used herbal medicine in 1997, as reported in Journal of American Medical Association).
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Important sources for new drug discovery (1/3 of top selling drugs in the
market derived from herbal ingredients, as reported in Drug Discovery Today).
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Increased R&D investment in North America, Europe, Japan,
China, Taiwan, and Hong Kong. Singapore established a TCM
taskforce since 2000.
How Western Drugs Work?
Drug
Therapeutic Target (Disease related protein) => Beneficial effect
Toxicity and side-effect inducing proteins => Adverse effects
One drug, single therapeutic target
Drug optimized
with the best therapeutic effect
How Herbal Products Work?
Synergy of Multiple Herbal Ingredients Aganist Multiple Targets
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Mixture of multiple herbs:
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Synergy:
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Actions > Simple sum
Mutual enhancement
Mutual counteraction
Maintenance and balance
Multiple targets:
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Therapeutics
Symptom treatment
Toxicity/side effect modulation
Drug delivery and clearance
Boost of immune system
Energy, PH, temperature balance/restoration
Harmonization
Pharmacology & Therapeutics 2000, 86:191-198
Why Mechanism of Herbal Products?
Current and future
work necessary to
advance herbal
medicines:
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Standardization in herbal
composition
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Scientific proof and
optimization
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Analytic chemistry
Need info about the
related targets
Discovery of novel
cocktail approaches:
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Need understanding of
how herbal ingredients
work in synergy.
Why Computer Approach?
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Existing experimental methods costly and time-consuming.
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Limited resources:
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Limited availability of herbs
Difficulty in chemical synthesis and bioassay.
Feasibility of computer approach:
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Information availability:
herbal ingredients, disease and toxicity related proteins.
Software technology:
INVDOCK and machine learning.
Computer capacity:
Higher speed and lower cost
How It Works?
Computer Match-Making
Therapeutic Target
Herbal
Formula
Database
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Herbal
Ingredient
Database
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Herbal
Ingredient
Computer Toxicity Target
Match-Making
Software
ADME protein
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Therapeutic
Target
Database 
Drug Adverse
Reaction
Target
Database 
Matched Pairs
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
Gingko as An Example:
Ingredients in Its Leaf Extract
Flovone glycosides
(flavonoids)
Terpene lactones
(terpenoids)
Quercetin, kaempferol, isorhamnetin, ginkgetin….
Ginkgolides: A,B,C, J and M…
Bilobalides: A, B …..
Phenols
Ginkgolic acid, hydroginkgolic acid, ginkgolinic acid,
ginkgol, bilobol….
Organic acids
Alcohol groups
Quinic acid, linoleic acid, shikimic acid, asorbic acid,
formic acid, propionic acid…
hexenol, sequoyitol
Vitamins and others
Vc, carotenoids, iron….
More than 45 compounds found so far.
Gingko as an Example:
Query Results from HICD
Gingko as an Example:
Query Results from HICD
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Selection criterion
Gingko as an Example:
Query Results from Database Search
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Structure of Important Active Ingredients
in Gingko Leaf Extract
Identified Therapeutic Targets of Quercetin
Identified Theraputic
Targets By computer
Experimental Findings
Target status
Therapeutic Implication
Phospholipase A2
Potent inhibitor to group
II PLA2
Confirmed
Inflammation, Neuro-related disease
Protein Kinase C
Inhibits the
phosphorylating activity
Implicated
Heart disease, Cancer, Stress related,
Brain disease, Asthma
Estrogen Receptor
Binds to type II estrogen
binding site
Confirmed
Breast Cancer
Inhibit p38 MAPK
activity
Implicated
Arthritis, Asthma
MAP Kinase
Y. Z. Chen, etc. American Journal of Chinese Medicine, 30, 139-154.
(2002).
Predicted and Observed Therapeutic Effects
of GingKo
Therapeutic Effects of Identified
Therapeutic Targets
Therapeutic Effects Observed
Memory and learning enhancement
Treatment of memory loss
Anti-cancer
Anti-arthritis
Anti-Inflammation
Treating heart disease
Treating asthma
Beneficial to Gastric, colorectal, pancreatic cancer
Dose-dependant inhibition arthritis (only 1 report)
Treatment of bladder inflammation
Contribution to cardiovascular disease
Remedy against asthma, coughs
Neuro-protective function
Slowing down the progression of Alzheimer’s disease
Indigestion improvement
No report
Improvement of Vaso-dilation/contraction
Stimulation of blood circulation
Comparison Between
Prediction and Experiments
Medicinal Plant
Potential Therapeutic Targets
Identified
Experimentally
Confirmed and
Implicated So Far
Percentage
Gingko
37
19
51%
Ginseng
(ginsenosides)
Serenoa Repens
6
5
83%
35
24
69%
16
14
88%
Citrus Fruit
(Flavonoids)