international research collaboration and scientific publication · 2016. 8. 30. · daun sembung...
TRANSCRIPT
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International Research Collaboration and Scientific Publication
Pharmacological and Genomic Spaces Network for Drug Target Identification
of Antidiabetes Jamu Formula
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What is Jamu?
• Jamu is an Indonesian herbal medicine made from a mixture of several plants.
- Jamu Kunyit Asam -Useful during menstruation: reducing the pain, promotes menstrual flow
Ingredient:• Turmeric (Curcuma domestica) Emmenagogue• Tamarind (Tamarindus indica) Analgesic• Nutmeg (Myristica fragrans) Sedative• Cinnamon (Cinnamomum burmannii) Carminative Source: Anonim, Herbal Indonesia Berkhasiat: Bukti
Ilmiah dan Cara Racik, Prepared by Redaksi Trubus, Depok: PT Trubus Swadaya, 2009.
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Drug development
• One drug one target
• Multi drug network target
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Prostaglandin G/H synthase 2
Paracetamol
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Network Pharmacology
Chemical
C1
C2
C3
CJ
Protein
P1
P2
P3
PK
P4
… …
Plant
P1
P2
PI
…
Gene Onthology
G1
G2
G3
GL
G4
…
Network pharmacology is an approach to drug design that encompasses systems biology, network analysis, connectivity, redundancy and pleiotropy
Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery (2008) Nature Chemical Biology, 4 (11), pp. 682-690 4
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Previous works: (1) PLS-DA of Jamu ingredients
Yih = 0h + 1h x1i + 2h x2i + … + 1h x1i + ih
URI DOA DMB GST FML MSC PIN RSP WND
J1 0.53 -0.15 0.03 0.47 0.15 -0.21 -0.35 0.33 0.41
P1 0.12 0.37 -0.16 -0.30 0.43 0.32 0.19 0.22 0.30
Total correct classification: 71.6%
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Previous works: (1) N-PLS-DA of Jamu ingredients
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Developing New Jamu Formula
• Based on previous model (PLS-DA and N-PLS-DA) and hypothesis of Jamu formula structure
• Focusing on cholesterol and diabetes
Analgesic Antimicrobial AntiinflammatoryTarget specific
activity
Anticholesterolemic Hypoglicemic
List plants with those activities Select plant that easy to obtain
Step 1
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Jamu P0001 P0002 P0003 P0004 … P0465 Predicted Efficacy
J001 1 0 1 0 … 1 GST
J002 0 1 1 1 … 0 DOA
… … … … … … … …
J050 0 0 0 1 … 1 FML
Select formula with the following predicted efficacyDiabetes GSTCholesterol DOA
Step 2 Combine plants from Step 1 into 50 new Jamu formula
Step 3
Daun Sembung(Blumea balsamifera)
Bratawali(Tinospora crispa)
Ginger (Zingiber officinale)
Bitter Melon (Momordica charantia)
Bidara upas(Merremia mammosa)
Jati Belanda (Guazuma ulmifolia)
Kumis Kucing(Orthosiphon aristatus)
Kemuning(Murraya paniculata)
Diabetes
Cholesterol
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Principle of DrugCIPHER
Tanimoto Coefficient
Anatomical Therapeutic Chemical Classification System
CS(DxD)
Drug Protein closeness
(DxP)Concordance score:The likelihood of a protein being targeted by a drug
(DxP)
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Collecting plant’s secondary metabolite
• Database source: – KNApSAcK family databases
(http://kanaya.naist.jp/KNApSAcK/),
– The Dictionary of Natural products (DNP) databases(http://dnp.chemnetbase.com)
• Searching for chemical structure: Pubchem Compoundhttp://www.ncbi.nlm.nih.gov/pccompound
Plant KNApSAcK DNP Total
Ginger (Zingiber officinale) 101 190 291
Brotowali (Tinospora Crispa) 6 12 18
Sembung (Blumea Balsamivera) 12 29 41
Bitter Melon (Momordica Charantia) 63 182 245
Total 182 413 595
http://kanaya.naist.jp/KNApSAcK/http://dnp.chemnetbase.com/http://www.ncbi.nlm.nih.gov/pccompound
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Collecting protein targeted by the chemical compound
• Database source: Pubchem Database (https://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi)
Chemical: 57
connection: 3059 Protein: 478
https://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi
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Summary of the dataset
Plant Total chemical
Chemical with known protein
target
Chemical-protein
connection
Protein target
Ginger (Zingiber officinale) 291 47 2821 415
Brotowali (Tinospora Crispa) 18 3 70 69
Sembung (Blumea
Balsamivera)41 4 1098 348
Bitter Melon (Momordica
Charantia)245 4 93 36
Total 595 58 4082
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Next step…
Chemical similarity
Protein-protein interaction
Chemical-protein closeness
Action ingredients Combinatorial rules (synergistic) Understanding the action mechanisms
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Action Ingredients
P(56xP)
Concordance score
4 plants in diabetes Jamuformula
P(19xP)
Chemical drug for diabetes(Drugbank)
For each chemical compound, 100 protein with highest concordance score is selected.
The matrix is reduced to (75x1250)
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Action Ingredients
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Action Ingredients
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Action Ingredients
P(75x1250)
D(75x75)
Concordance score Distance
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Synergistic Effect
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NIMS (Network target-basedIdentification of Multicomponent Synergy)
Protein target closeness Phenotype (disease) similarity score
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Synergy scoreTopology score Agent score
Synergy score
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Testing the Synergy Score: Permutation Test
Observed P1 P2 P1000
Correlation: r
r
P-value
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Synergistic Effect: P-value
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Next…
Chemical
C1
C2
C3
CJ
Protein
P1
P2
P3
PK
P4
… …
Plant
P1
P2
PI
…
Gene Onthology
G1
G2
G3
GL
G4
…