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Automatic Generation of Drug Metabolic Pathways from ADME
Ontology on OWL-DL
Konagaya AkihikoRIKEN Genomic Sciences Center
Project DirectorAdvanced 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
PrimitivesBody/Cell
Approaches for Metabolic Pathway Models• Static Approach • Dynamic Approach
Generated from primitive reactions depending on “Trigger”
Trigger
KEGG
http://www.genome.jp/kegg/
A Priori Defined
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
Real Rainbow Color
All the colors you can see with your own eyes!
From 360 nm~ 400 nm to 760 nm~ 830 nm
Explicit Knowledge of Colors
Red
Yellow
Green
Blue
Indigo
Purple
Orange
Ontology for Rainbow Colors
#800080 RGB Value
#000080
#0000FF
#008000
#FFFF00
#FF8000
#FF0000 Red
Yellow
Green
Blue
Indigo
Purple
Orange
Color Representation by Primitives
R: 700nm,G: 546.1nm,B: 435.8nm.
RGB Representation
??Purple Red360nm 830nm???
Ontology Schema
POC
ProcessMolecular Level
EnzymaticReaction
Protein Binding
Migration
Molecular Event
Inhibition
Independent entities
Molecule
Organ
Cellularregion
Intension (Process) Extension(Object)
Dependent entities
has_participant Continuant
Attribute (Continuant)
hasSubProcesses(Asserted by OHDAG)
located_in
DID
Generatedpathways
Detecteddrug-drug interaction
Inference Program
Hypothetic Assertion
Drug Interaction Ontology
(Asserted by OHDAG)
Pathway
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)
Resultant(SN-38@lever)
Process(Irinotecan-SN38 Metabolism@lever)
Prototype System
UI(Java)
InferenceProgram
(SWI-Prolog)dio_KCZ.owl
VisualizationProgram (Java)
Graph(png / ps)
result.owl
USERDot
Graphviz
Pathway Object Constructor
Drug Interaction Detector
SemwebLibrary
SWI-Prolog
dio_cpt-11.owl
dio_event.owl
DIO
Controlled Vocabulary
fma:Vein fma:Portal_vein
Organ_part fma:Artery
cytoplasmintracellular
Proteins Albumins
Enzymes
transport_protein
Biomolecule
hexosyltransferase Glucuronosyltransferase
Transferase
Glycine_conjugation
phase_II_drug_biotransformation
Water_conjugation
Methylation
Acetylation
Sulfate_conjugation
Glycosylation
glutathione_conjugation_reaction
Channel_diffusion
Passive_Transport
Carrier_Mediated_diffusion
Diffusion
Filtration
fma:Liver
fma:Solid_organ
fma:Lung
fma:Pancreas
fma:Kidney
fma:Organ
fma:Cavitated_organ
cellular_component
cell
extracellular_region
independant_entities
fma:Anatomical_structure
Chemicals
fma:Body_substance
Deacetylketoconazole
Metabolites_of_Ketoconazole N-deacetyl-N-hydroxy_ketoconazole
Ketoconazole-CYP3A4DrugProteinComplex
SN38-Albumin
Ketoconazole-Albumin
membrane plasma_membrane
Vein_to_Artery
fiat_parts_migration
intestinal_lumen_to_outside_the_body
bile_to_Intestinenal_lumen
Artery_to_Vein
Ureter_to_outside_the_body
DeacetylationHydrolysis
CYP3A4Cytochrome_P450
ValueChange
Decreased
Maintained
Increased
dependant_entities
fma:Anatomical_cavity
Oxidoreductase
Cytochromes
Oxygenases
ESTERASE
Hydrolase
Isomerase
phase_I_drug_biotransformation
Oxidation
Reduction
DrugCellularProcess
ProcessDrugOrganismal
Process
DrugMolecularProcess
Drugs
Irinotecan
Ketoconazole
DrugOrMetabolite
Metabolites
P-gp
Membrane_Transport_Proteins MRP1
MRP2
OATP-C
fma:Lumen_of_common_bile_duct
fma:Organ_cavity_subdivision fma:Lumen_of_intestine
fma:Organ_cavity fma:Lumen_of_ureter
fma:Large_Intestine
fma:Gallbladder
fma:Small_intestine
fma:Ureter
UGT1A1
UGT1A7
Carboxylesterase
SN-38
Metabolites_of_Irinotecan APC
NPC
SN-38G
Beta-glucuronidaseGlycoside_Hydrolases
Continuant
basolateral_plasma_membrane
apical_plasma_membrane
passage_through_biological_membrane
Active_transport
Deacetylase
Enzymatic_ReactionotherEnzymaticReaction
MolecularProcess
BindingReleaseReaction
Migration
Secondary_active_transport
Primary_active_transport
fma:Feces
fma:Urine
FMO
AggregationOfMolecularProcess
DrugReleaseReaction
DrugBindingReaction
Inhibition
Facilitation
Generated PathwayArtery
Lumen_of_common_bile_duct
Portal_vein
Urine
Vein
Liver
Lumen_of_intestine
Ureter
Feces
Small_intestine
Kidney
Irinotecan
TR0000033
ET
Irinotecan
R
TR0000032ET
TR0000031ET
TR0000042ET
Irinotecan TR0000045ET
Irinotecan
R
TR0000019ET
TR0000012ET
TR0000021ET
TR0000030ET
TR0000005ET
TR0000006
ET
R
R
Irinotecan
R
TR0000044ET
TR0000043
ET
SN-38R
CarboxylesteraseES
TR0000018ES
TR0000017
ET
TR0000035ET
TR0000007
ETNPCRCYP3A4ES
ES ETAPCR
R
Irinotecan
R
P-gpES
TR0000026ET
R
MRP2 ESES
TR0000008ES
IrinotecanR
TR0000046ET
R
SN-38GR
UGT1A1
ES
ET
SN-38
R
TR0000013ET
TR0000041
ET
TR0000009
ET
SN-38
R
TR0000024ET
R
Irinotecan
R
TR0000034ET
TR0000010
ET
IrinotecanR
SN-38G
R
TR0000025ET
SN38-AlbuminR
AlbuminsES
TR0000014ET
SN-38
R
TR0000022ET
TR0000036ET
R
OATP-CES
SN-38
R
TR0000028ET
TR0000011
ET
IrinotecanR
Irinotecan
R
TR0000020ET
TR0000039ET
SN-38G
R
TR0000016ET
TR0000029ET
R
R
SN38-AlbuminR Albumins
ES
TR0000023ET
SN-38
R
TR0000037ET
TR0000038
ET
SN-38
R
SN-38
RTR0000015
ET
TR0000001ET
TR0000002ET
TR0000003ET
R
CarboxylesteraseES
R
R
Beta-glucuronidase
ES
SN-38GR
RR
SN-38R
TR0000040ET
R
SN-38GR
UGT1A1ES TR0000004
ET
RP-gp ES
R
MRP2
ES
ES
SN-38R
MRP1ES
TR0000027ET
SN-38R
R
R
Detected Drug Interactions
Bile
Liver
Irinotecan@liver CE@liver
TR0000019
SN-38@liver
SN-38@liver MRP2@liver
TR0000007
SN-38@bile
Irinotecan@liver CE@liver
TR0000019
SN-38@liver MRP2@liver
TR0000007
SN-38@bile
Irinotecan
SN-38
SN-38
MRP2
CE
a) Pathway maprepresentation
b) Modules of the pathway(Molecular events)
c) Connection of modules(Pathway)
T S
R
R
T S
R
T S
R
T S
Ontology-driven Hypothetical Assertion
is_ainstance_of
instance_ofhasSubProcesses
is_ainstance_of
instance_ofhasSubProcesses
Process
DrugMolecularProcess
MolecularProcess Aggregation_of_MolecularProcess
Enzymatic_Reaction BindingReleaseReaction Inhibition
Oxidationddi0 ddi1 ddi2 ddi3Drug_BindingReaction
CYP3A4CPT11
APC
Phase_I_Drug_Biotransformation
CYP3A4KCZ
KCZ/CYP
CYP3A4CPT11
NPC
AlbuminSN-38
SN-38/Alb
AlbuminKCZ
KCZ/Alb
AlbuminSN-38
SN-38/Alb
AlbuminKCZ
KCZ/Alb
in liver in vein in artery
HypotheticalAssertion
TR0000021 TR0010001 TR0000012 TR0000013 TR0010006 TR0000022 TR0010007
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 GSCRyuzo Azuma RIKEN GSCTakeo Arikuma Tokyo Institute of TechnologyKentaro Watanabe Tokyo Institute of Technology (Hitachi Ltd., Japan. )Kazumi Matsumura RIKEN GSC (DAIICHI PURE CHEMICALS CO., LTD., Japan. )