September 10, 2009

11:41

WSPC - Proceedings Trim Size: 9.75in x 6.5in

giw2009-master

212

REPRESENTATION AND ANALYSIS OF MOLECULAR
NETWORKS INVOLVING DISEASES AND DRUGSMINORU KANEHISA1,2kanehisa@kuicr.kyoto-u.ac.jp
1 Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Ky-oto 611-0011, Japan
2 Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

Abstract
Twenty years ago the Human Genome Project was initiated aiming to uncover
the genetic factors of human diseases and to develop new strategies for diagnosis,treatment, and prevention. Despite the successful sequencing of the human genome
and the discovery of many disease related genes, our understanding of molecularmechanisms is still largely incomplete for the majority of diseases. In the KEGG
database project we have been organizing our knowledge on cellular functions andorganism behaviors in computable forms, especially in the forms of molecular networks (KEGG pathway maps) and hierarchical lists (BRITE functional hierarchies).
The computerized knowledge has been widely used as a reference for biological interpretation of large-scale datasets generated by sequencing and other high-throughput
experimental technologies. Our eﬀorts are now focused on human diseases and drugs.
We consider diseases as perturbed states of the molecular system that operates thecell and the organism, and drugs as perturbants to the molecular system. Since theexisting disease databases are mostly for humans to read and understand, we develop
a more computable disease information resource where our knowledge on diseases
is represented as molecular networks or gene/molecule lists. When the detail of themolecular system is relatively well characterized, we use the molecular network representation and draw KEGG pathway maps. The Human Diseases category of theKEGG PATHWAY database contains about 40 pathway maps for cancers, immunedisorders, neurodegenerative diseases, etc. When the detail is not known but disease genes are identiﬁed, we use the gene/molecule list representation and createa KEGG DISEASE entry. The entry contains a list of known disease genes andother relevant molecules including environmental factors, diagnostic markers, andtherapeutic drugs. The list simply deﬁnes the membership to the underlying molecular system, but is still useful for computational analysis. In the KEGG DRUG
database we capture knowledge on two types of molecular networks. One is theSeptember 10, 2009

11:41

WSPC - Proceedings Trim Size: 9.75in x 6.5in

giw2009-master

Representation and Analysis of Molecular Networks Involving Diseases and Drugs

213

interaction network of drugs with target molecules, metabolizing enzymes, transporters, other drugs, and the pathways involving all these molecules. The other isthe chemical structure transformation network representing the biosynthetic pathways of natural products in various organisms, as well as the history of drug development where drug structures have been continuously modiﬁed by medicinal chemists.
KEGG DRUG contains chemical structures and/or chemical components of all prescription and OTC drugs in Japan including crude drugs and TCM (TraditionalChinese Medicine) formulas, as well as most prescription drugs in USA and manyprescription drugs in Europe. I will report on our strategy to analyze the chemical architecture of natural products derived from enzymatic reactions (and enzymegenes) and the chemical architecture of marketed drugs derived from human madeorganic reactions in the history of drug development, towards drug discovery fromthe genomes of plants and microorganisms.