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Drug Drug Interaction Prediction through Systems Pharmacology Analysis

Tatonetti Lab
at Columbia University Medical Center

Sun1, Nicholas P. Tatonetti1 Department of Biomedical Informatics, Columbia University, New York, NY

Drug-drug interactions (DDI) is important! -play an important role in explaining drug side effects and facilitating drug design. DDI mechanism -integrative pathway analysis advances our understanding of DDI by revealing the molecular basis of drug action.

1. Get drug, gene, pathway data from KEGG and Drugbank.

Drug-drug interactions
121 unique drugs 5202 unique DDIs
drug1 Desipramine drug2 Labetalol Isoetharine Levobunolol Esmolol Oxprenolol Risperidone Penbutolol Isoproterenol Nadolol Danazol Desipramine Dibucaine Diprenorphine Dobutamine


6000$ 5000$ 4000$ 3000$ 2000$ 1000$ 0$ >0$ >2$ >4$ >8$ 143$ 5202$ 3943$ 2726$ >0$ >2$ >4$ >8$



Gene ID

3098 Alpha-D-Glucose-6-Phosphate 3098 Beta-D-Glucose 3098 Adenosine-5'-Diphosphate 2821 Erythose-4-Phosphate 2203 Adenosine monophosphate 2597 NADH 2597 NicoInamide-Adenine-DinucleoIde 5315 Pyruvic acid 5313 Pyruvic acid

Drug ID
DB02007 DB02379 DB03431 DB03937 DB00131 DB00157 DB01907 DB00119 DB00119

Desipramine Desipramine Desipramine Desipramine Desipramine Desipramine Desipramine Desipramine Atropine Atropine Atropine Atropine Atropine

DDI prediction -The emergence of pharmacogenomics knowledge bases (PharmGKB and DrugBank) and pathway databases (KEGG), provide an opportunity to improve DDI prediction methods


2. Integrate data

hsa00010 hsa00010 hsa00010 hsa00010 hsa00010 hsa00010 hsa00010 hsa00010

True positive rate ROC area =0.67

3. Find pathway pairs that share at least one gene.
gene_id a_pathwayid 18 hsa00250 25 hsa04012 26 hsa00330 27 hsa04012 31 hsa00061 32 hsa00061 34 hsa00071 35 hsa00071 36 hsa00071 38 hsa00071 39 hsa00071 90 hsa04060 91 hsa04010 94 hsa04060 100 hsa00230 107 hsa00230 113 hsa00230 124 hsa00010 125 hsa00010 b_pathwayid hsa00280 hsa04110 hsa00340 hsa05416 hsa00620 hsa00620 hsa00280 hsa00280 hsa00280 hsa00072 hsa00072 hsa04350 hsa04060 hsa04350 hsa05340 hsa04020 hsa04020 hsa00071 hsa00071

False positive rate

Drug-Class Interactions

4. Download detail pathway files from KEGG and convert them to text format.
*The pathway are not represented as a complete path but individual interactions.

From To Relationship 356 355 activation 8743 8793 activation 5566 57 inhibiton ... ... ... ... ... ...

5. Construct pathways as python sets with genes comprising them.

*Each pathway has multiple path leading from the first upstream gene to the sharing gene for the two pathways.
hsa04012 [ [['374', '1956', '1398', '25'], ['374', '1956', '1399', '25']], [['2069', '1956', '1398', '25'], ['2069', '1956', '1399', '25']], [['685', '1956', '1398', '25'], ['685', '1956', '1399', '25']]] hsa04360 [['1945', '2046', '25'], ['1945', '285220', '25']], [['2050', '25']], [['2046', '25']], [['2047', '25']], [['2044', '25']], [['2045', '25']], [['2042', '25']], [['2043', '25']], [['2041', '25']], [['2048', '25']]]

: Genes in the left pathway : Genes in the right pathway : Genes shared by both pathways

: Interactions between genes : Drug interact with genes

Class-class Interactions

Assumption: If two pathways come across each other, the drug that target the upstream of the two pathways will likely to interact each other and form a DDI pair. Explanation: In this case, the left pathway is targeted by drug A and right pathway is targeted by drug B. Since drug effect signal pass downstream, the shared genes by the two pathways get mixed signals from two drugs. This may cause unexpected changes in the drug response. The two drugs here are hypothesized to form a drug-drug interaction pair.

6. Link drugs to the genes in pathways pairs and produce DDI pairs. *If the drug A targets one gene in one of the pathway pair. Drug B targets one gene in the other pathway of the pair. Then drug A and drug B forms a DDI.

N06 (Psychoanaleptics) tends to interact with nerve system drugs L01 (Antineoplastic agents) tends to interact with antineoplastic agents

Conclusions and discussion

1.Two random drugs will have somewhat interactions more than half of the time. Drug of similar class tend to interact with each other. 2.The incompleteness of pathway data is limiting the research result. 3.Standardization is still a big issue in data integration.

1.Data from KEGG and Drugbank are biased and sparse. Model is not determinant. 2.Didnt filter compounds (not drugs) from the database.

Future Work:
1. Filter results, improve model. 2. Combine EHR clinical data to confirm the hypothesis. 3. Look into other discoveries from the results.

Department of Biomedical Informatics Columbia University Medical Center 622 West 168th St. VC5 New York, NY 10032 Contacts: Xiaochen Sun 6464603859 Nicholas P Tatonetti Pantone 212-305-2055


Tatonetti Lab
at Columbia University Medical Center

Wednesday, April 3, 13