Professor,
Graduate School of Pharmaceutical Sciences,
Kyoto University

Novel drug discovery based on the genomic information


     About 3 billion base pairs of the human genome was completely sequenced. However, there still is a lot of works remained to do for understanding what kind of role for each gene to play. The genomic drug discovery science is the science field of discovery of the new drug, the medicine of the effect to be higher and the medicine with few side effects, using the genome information.



1. Functional genomics of G protein-coupled receptors (GPCR)
Information from genome sequencing estimated the existence of 700-800 GPCRs in the human genome: about 250 of GPCRs are identified as receptors for known ligands, and the rest are still orphan receptors (oGPCRs). Recognized for the potential of oGPCRs as targets of novel drug discovery, oGPCRs have attracted a tremendous level of attention in terms of continued identification of their endogenous ligands and elucidation of their physiological functions.
Attempts to study the targeted molecule distribution at the subcellular level have been limited by the lack of specific structural probes of GPCRs. Functional GPCR-GFP (green fluorescent protein) fusion molecules are important tools for optical measurement of biochemical and biophysical processes that are relevant to the signal transduction of GPCRs (Figure 1). Very recently, we successfully identified natural ligand (free fatty acid) for orphan GPCR GPR120. GPR120 localizes in the intestinal tract and regulates the secretion of the most potent insulin-secreting peptide hormone GLP-1; hence, this GPCR would be a good candidate for anti-diabetic drugs (Figure 2).

Fig.1. Cell-base screening system for ligand fishing		Fig. 2. Successful de-orphaning of GPR120



2. Functional genomics by microarray DNA Chip

     A microarray is one of the most important basic technology for drug discovery from the aspect of genomics (Figure 3). The focus of genome research will be shifted to functional analysis of genes including the determination of precise transcript unit as transcriptome. The gene expression pattern (i.e. profile) of disease specific status could be obtained by DNA chip technology that makes it accelerate to find candidate molecules of drug target. We are interested in the construction of databases of gene expression data, gene expression analysis of disease model animals and human disease status (such as cancer, nephritis, diabetic nephropathy, etc), and finally discovering the candidate molecule of the effective novel drug target and revealing the mechanisms of human disorders.

Fig. 3. Microarray