International Research Collaboration and Scientific Publication

Pharmacological and Genomic Spaces Network for Drug Target Identification

of Antidiabetes Jamu Formula

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.

2

Drug development

• One drug one target

• Multi drug network target

3

Prostaglandin G/H synthase 2

Paracetamol

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

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

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

8

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

9

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)

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

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

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

Next step…

Chemical similarity

Protein-protein interaction

Chemical-protein closeness

Action ingredients Combinatorial rules (synergistic) Understanding the action mechanisms

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)

Action Ingredients

Action Ingredients

Action Ingredients

P(75x1250)

D(75x75)

Concordance score Distance

Synergistic Effect

NIMS (Network target-basedIdentification of Multicomponent Synergy)

Protein target closeness Phenotype (disease) similarity score

Synergy scoreTopology score Agent score

Synergy score

Testing the Synergy Score: Permutation Test

Observed P1 P2 P1000

Correlation: r

r

P-value

Synergistic Effect: P-value

Next…

Chemical

C1

C2

C3

CJ

Protein

P1

P2

P3

PK

P4

… …

Plant

P1

P2

PI

…

Gene Onthology

G1

G2

G3

GL

G4

…