データ統合と計算の融合による創薬研究	  水口 賢司
http://mizuguchilab.org
kenji@nibiohn.go.jp

Outline	- Phenotypic and target-based screening withligand-based and structure-based drug design- Systems biology based approach- Data integration- Application to cancer drug discovery

Phenotypic screening and targetbased screening	

http://www.sulsa.ac.uk/research-facilities/uk-npsc/phenotypic-screening	Ligand based drug design (LBDD)
Actives	
1 0 1 1 0 1 1	Fingerprints	

A largecompound library	Phenotypicscreening	Pharmacophore
QSAR	

Inactives	

http://www.shirokawa.jp/column/amakura_yoshiaki/366/	Structure based drug design (SBDD)
Target	A large compound library/database

Docking
Scoring	

List of compounds forassays	How SBDD can assist target-based
screening 	
P1	e.g., FXa inhibitors	

NA basic fragment at P1 site was shown to be
essential for mimicking the natural substrateby ligand based approaches

NN

Dabigatran	

O

Ligand based

ONN

N

N

Structure based

Rivaroxaban	

O

Unfavorable ADMETprofiles(Poor oral bioavailability)	

A neutral fragment→ Favorable ADMET profiles	

SBDD solved the problem with LBDD	Fundamental limitations of structurebased approaches	
Adverse event	

SBDD	

Target 	Multi-targeting
activities	
Hit	The systems biology approach todrug discovery

Source: Ingenuity Pathway Analysis, Causal Network Analysis suite

Prathipati and Mizuguchi, Current Topics in Medicinal Chemistry (in press)	

Data integration
Pathway	Protein-compoundinteractions

Gene	(Predicted) structure	Chemical compound	Protein	
Integration using InChI	
PubChem
PubChem
PubChem3016	
PubChem
3016	
3016	
3016	
ChEBI	
49575	AAOVKJBEBIDNHE	

Diazepam	
C16H13ClN2O	
PDB
DZP	

DrugBank	
DB00829	
DrugBank	DB07699	

Data warehouse system	

A Data warehouse compiles the contents of multiple databases to fit acommon data model (Stein 2003, Nat Rev Genetics 4, 337-345)

Toxygates: an integrated platform fortoxicogenomics data analysis	
http://toxygates.nibio.go.jp/

RDF (remote/local)
Gene, protein, pathway, ...	

Pathway	Time	Compound B	

Dose	 Time	 Dose	

Sample	Sample	Samples (〜24,000)	

Gene	
Probe	

Gene	

Dynamic lookup
from remote servers	

Nystrom et al., Bioinformatics (2013)

Probes (〜30,000)	

Probe	（）	Data matrix (key-value store, Kyoto Cabinet)	
1	 2	

3	 4	 …	ranking	(microarray data)	

Compound A	TargetMine	
Data warehouse for drug target
prioritization	
http://targetmine.mizuguchilab.org• Integrate a wide range of data sources.
• Enable complicated searches that are
difficult to achieve with existing tools.
• Custom annotations and in-house data.
Powered by		at the Cambridge Systems Biology Centre

Chen et al., PLoS ONE 6(3): e17844 (2011)

Data sources in TargetMine	
micro	  RNA	  &	  Transcrip7on	  factor	  target	  associa7ons	 target	  associa7ons	

Pathways	  &	  	  interac7ons	

Genes	  &	  proteins	

Domains	  &	  	  3D	  structures	

iRefIndex	

Chemical	  compounds	  	  &	  interac7ons	

INTEGRATION	
Homo sapiens, Rattus norvegicus, Mus musculus

How InterMine integrates data
Drug

Disease Ontology

Protein
Protein

Protein
Gene

Gene
Gene
Pathway

Gene OntologyDrug

Disease Ontology

Protein

Gene
Pathway

Gene OntologyPost-processing(Java, PostgreSQL)

Gene OntologyGiven a protein, find all the compounds that target this protein
Query protein: Catechol O-methyltransferase (COMT_HUMAN)	

36	  non-­‐redundant	  interac7ng	  compounds	  from	  ChEMBL,	  DrugBank	  and	  PDB	  14	  interac7ng	  compounds	  7	  interac7ng	  compounds	  17	  interac7ng	  compounds	  ChEMBL	
14	15	 2	 5	DrugBank	PDB	Given a drug, find all the ChEMBL targets that have been
co-crystalized with that drug

Found	  4	  proteins	Targeting cancer stem cells using asystems biology approach	Philip Prathipati	In silico スクリーニングコンテスト
Wetなキナーゼアッセイで活性が認められる化合物を同定
2014年7月18日

Chiba et al., Scientific Reports (in press)