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

What is a pathway?

Pathway KEGG

Metabolic Pathway

http://www.expasy.org/cgi-bin/show_thumbnails.pl

Typical Pathway Analogy

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

How many colors can you see in rainbow?

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

Which are Purple?

#800070

#800060

#500080

#800050 #700080

#600080#800080

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)

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

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. )

ご静聴ありがとうございました。

Thank You for Listening