Automatic Generation of Drug
Metabolic Pathways from ADME
Ontology on OWL-DL
Konagaya Akihiko
RIKEN Genomic Sciences Center
Project Director
Advanced Genome Information
Technology Research Group
Motivation
•Coming of Personalized Genome Era
•Polymorphism in Drug Response Genes
•Detection of Drug-Drug Interaction
In silico prediction of individual differences
in drug response and drug-drug interactions
on multiple dose
Issues
•
•
•
Detection of Personal Genome Variation
Inference of Drug-Drug Interactions on
Multiple Dose
Quantitative Analysis by Drug Metabolic
Pathway Simulation
What is a pathway?
Pathway
KEGG
Metabolic Pathway
http://www.expasy.org/cgi-bin/show_thumbnails.pl
Typical Pathway Analogy
Approaches for Metabolic Pathway
Models
• Dynamic Approach
• Static Approach
Generated from
primitive reactions
depending on “Trigger”
A Priori Defined
Trigger
Primitives
KEGG
http://www.genome.jp/kegg/
Body/Cell
Why Dynamic Approach?
•Combinatorial Explosion of Molecular
Pathways
•Integration of Continuants and Processes on
Primitive Molecular Interactions
•Representation of Pathways as Aggregation
of Primitive Molecular Events
How many colors can you see in rainbow?
Real Rainbow Color
From 360 nm～400 nm
to 760 nm～830 nm
All the colors you can see with your own eyes!
Explicit Knowledge of Colors
Purple
Indigo
Blue
Green
Yellow
Orange
Red
Ontology for Rainbow Colors
Purple
RGB Value
#800080
Indigo
#000080
Blue
#0000FF
Green
#008000
Yellow
#FFFF00
Orange
#FF8000
Red
#FF0000
Which are Purple?
#800050
#800060
#800070
#700080
#800080
#600080
#500080
Color Representation by Primitives
RGB Representation
R: 700nm,
G: 546.1nm,
B: 435.8nm.
Purple ?
360nm
???
Red
830nm
Ontology Schema
Intension (Process)
Extension
Process
Molecular Level
Molecular Event
Enzymatic
Reaction
Migration
Protein Binding
Pathway
Inhibition
Attribute (Continuant)
(Object)
has_participant
Continuant
Independent entities
located_in
Molecule
Cellular
region
Organ
Dependent entities
hasSubProcesses
(Asserted by OHDAG)
DID
POC
(Asserted by OHDAG)
Hypothetic Assertion
Drug Interaction Ontology
Detected
drug-drug interaction
Generated
pathways
Inference Program
基本要素インスタンスによる
静的クラス（continuants)と動的クラス(process)
の統合
「プロセス」を定義するために必要十分な「物」の関係
Trigger
(SN-38@lever)
Situated
(Carboxyl esterase@lever)
Process
(Irinotecan-SN38 Metabolism@lever)
Resultant
(SN-38@lever)
基本要素インスタンスの
重合による現実世界の記述
薬相互作用オントロジーでの例（吉川、有熊、小長谷、２００６）
Prototype System
Inference
Program
(SWI-Prolog)
UI
(Java)
USER
Pathway Object Constructor
dio_event.owl
Semweb
Library
dio_cpt-11.owl
SWI-Prolog
DIO
Drug Interaction Detector
Visualization
Program (Java)
dio_KCZ.owl
result.owl
Dot
Graphviz
Graph
(png / ps)
Controlled Vocabulary
Glycine_conjugation
Water_conjugation
Methylation
phase_II_drug_
biotransformation
Acetylation
Sulfate_conjugation
Glycosylation
glutathione_
conjugation_reaction
Hydrolysis
phase_I_drug_
biotransformation
Enzymatic_Reaction
otherEnzymaticReaction
DrugCellular
Process
Process
DrugOrganismal
Process
DrugMolecular
Process
DrugReleaseReaction
Deacetylation
Oxidation
Reduction
Vein_to_Artery
BindingRelease
Reaction
DrugBindingReaction
intestinal_lumen_to_
outside_the_body
Migration
fiat_parts_migration
bile_to_Intestinenal_lumen
MolecularProcess
AggregationOf
MolecularProcess
Inhibition
Artery_to_Vein
Channel_diffusion
Facilitation
Ureter_to_outside_the_body
Carrier_Mediated_diffusion
Passive_Transport
Diffusion
Active_transport
Secondary_active_transport
passage_through_
biological_membrane
Filtration
Primary_active_transport
cell
cellular_component
extracellular_region
intracellular
cytoplasm
membrane
plasma_membrane
fma:Vein
fma:Portal_vein
basolateral_
plasma_membrane
apical_plasma_membrane
fma:Liver
Organ_part
fma:Artery
fma:Solid_organ
fma:Lung
fma:Pancreas
fma:Kidney
fma:Anatomical_structure
fma:Large_Intestine
fma:Organ
fma:Cavitated_organ
UGT1A1
fma:Gallbladder
hexosyltransferase
Glucuronosyltransferase
UGT1A7
Cytochromes
Cytochrome_P450
CYP3A4
Oxygenases
FMO
Transferase
fma:Small_intestine
independant_
entities
Chemicals
fma:Ureter
Oxidoreductase
Biomolecule
Proteins
Albumins
ESTERASE
Carboxylesterase
DrugProteinComplex
Ketoconazole-CYP3A4
Enzymes
Hydrolase
Glycoside_Hydrolases
DrugOrMetabolite
SN38-Albumin
transport_protein
Isomerase
Deacetylase
fma:Feces
Ketoconazole-Albumin
Drugs
Membrane_Transport_Proteins
fma:Urine
MRP1
Continuant
fma:Body_substance
P-gp
Irinotecan
Ketoconazole
Deacetylketoconazole
MRP2
N-deacetylN-hydroxy_ketoconazole
OATP-C
Decreased
dependant_
entities
Metabolites
ValueChange
Maintained
fma:Anatomical_cavity
fma:Organ_cavity_
subdivision
fma:Lumen_of_intestine
fma:Organ_cavity
fma:Lumen_of_ureter
Increased
Metabolites_of_Ketoconazole
fma:Lumen_of_
common_bile_duct
SN-38
Metabolites_of_Irinotecan
APC
NPC
SN-38G
Beta-glucuronidase
Generated Pathway
Artery
ET
SN-38
ET
TR0000022
R
R
ES
ET
SN38-Albumin
R
Albumins
TR0000023
TR0000036
R
ET
ET
Irinotecan ET
TR0000042
R
TR0000031
TR0000032
R
Kidney
SN-38
Irinotecan
Ureter
ET
ET
TR0000037
ET
TR0000044
ET
TR0000038
TR0000043
R
R
ET
SN-38
ET
Irinotecan
Urine
TR0000040
TR0000046
R
SN-38
R
Irinotecan
R
R
R
Liver
R
P-gp
CYP3A4
ES
ET
TR0000005
R
ES
TR0000021
ET
ES
ET
TR0000012
R
ET
APC
NPC
Carboxylesterase
TR0000030
ES
TR0000018
R
R
SN-38
R
UGT1A1
OATP-C
ES
ET
TR0000035
ET
ES
TR0000017
ET
TR0000019
MRP2
ET
Irinotecan
ET
ET
ES
ES
ES
R
SN-38G
TR0000008
TR0000007
R
R
TR0000006
TR0000009
ET
ES
Lumen_of_common_bile_duct
ET
R
SN-38G
ET
SN-38
ET
Irinotecan
ET
R
R
R
R
SN-38
Irinotecan
R
ET
ET
TR0000013
R
TR0000025
TR0000024
R
TR0000026
Vein
SN38-Albumin
ET
TR0000014
R
Albumins
ES
TR0000041
ET
TR0000033
R
R
Portal_vein
Irinotecan
R
SN-38
ET
ET
TR0000045
TR0000027
R
Small_intestine
Irinotecan
ET
TR0000039
ET
ES
TR0000020
R
MRP1
ES
ET
TR0000003
P-gp
ES
ET
TR0000001
SN-38
Carboxylesterase
MRP2
UGT1A1
ET
ES
ET
ES
R
R
R
TR0000002
TR0000015
R
ES
R
SN-38G
R
ET
TR0000004
R
Lumen_of_intestine
ET
ES
Beta-glucuronidase ET
SN-38G
Irinotecan
R
ET
ET
TR0000016
TR0000029
TR0000034
R
ET
SN-38 ET
R
TR0000028
TR0000011
R
Feces
SN-38
SN-38G
R
Irinotecan
TR0000010
Detected Drug Interactions
Irinotecan@liver
Irinotecan
T
Liver
Bile
MRP2
SN-38
a) Pathway map
representation
S
TR0000019
R
CE
SN-38
CE@liver
T
S
R
MRP2@liver
T
CE@liver
TR0000019
SN-38@liver
SN-38@liver
Irinotecan@liver
S
TR0000007
R
SN-38@bile
b) Modules of the pathway
(Molecular events)
SN-38@liver
MRP2@liver
T
S
TR0000007
R
SN-38@bile
c) Connection of modules
(Pathway)
Ontology-driven Hypothetical
Assertion
is_a
instance_of
Process
instance_of
hasSubProcesses
DrugMolecularProcess
MolecularProcess
Hypothetical
Assertion
Aggregation_of_MolecularProcess
Enzymatic_Reaction BindingReleaseReaction
Inhibition
Phase_I_Drug_Biotransformation
Oxidation
CYP3A4
CPT11
APC
TR0000021
ddi0
CYP3A4
KCZ
KCZ/CYP
TR0010001
in liver
ddi1
CYP3A4
CPT11
NPC
TR0000012
Drug_BindingReaction
Albumin
SN-38
Albumin
SN-38/Aｌｂ
TR0000013
KCZ
KCZ/Aｌｂ
TR0010006
in vein
ddi2
ddi3
Albumin
SN-38
SN-38/Aｌｂ
TR0000022
Albumin
KCZ
KCZ/Aｌｂ
TR0010007
in artery
Conclusion
• Drug Interaction Ontology can be represented
by OWL-DL in terms of processes, continuants
and events.
• Drug metabolic pathways can be dynamically
generated by the aggregation of primitive
molecular events with OWL-DL and Prolog.
• Drug interaction can be detected by logical
inference and mapped onto drug interaction
ontology.
Future Works
• Expansion of Drug Interaction Ontology
• Automatic Generation of ADME models
• Integration of Drug Interaction Ontology
and ADME simulation
Acknowledgement
Sumi Yoshikawa
RIKEN GSC
Ryuzo Azuma
RIKEN GSC
Takeo Arikuma
Tokyo Institute of Technology
Kentaro Watanabe Tokyo Institute of Technology (Hitachi Ltd., Japan. )
Kazumi Matsumura RIKEN GSC (DAIICHI PURE CHEMICALS CO., LTD., Japan. )
ご静聴ありがとうございました。
Thank You for Listening