Kenji Nagahari

The search for drug target molecules from genomics

Research methods for drug discovery have traditionally been empirically based. As an example, the knowledge that the willow tree contains an anti-in ̄ammatory substance led to the chemical synthesis of aspirin 100 years ago. Subsequent research then showed that cyclooxygenase was the target molecule of aspirin, and this ®nding in turn led to the development of enzyme inhibitors as anti-in ̄ammatory drugs 30 years ago. Recently the isozyme cyclooxygenase 2 was found to be induced by in ̄ammation, and inhibitors were subsequently developed as novel drugs with fewer gastrointestinal side-effects, e.g. gastric ulceration. In this way, research for drug discovery was based on very limited phenomena and molecules. Genomics, which has progressed rapidly over the past decade, is changing the methods of drug discovery. The human genome project has identi®ed 91.3% of the draft sequence, and is rapidly approaching its target of a complete sequence (http://www.ncbi.nlm.nih.gov/genome/ seq/). The number of genes in the human genome is estimated to be 30 000±40 000 [1] and new target molecules for drugs will be selected from among this large number of genes. However, the selection presupposes the elucidation of gene functions exerted by the gene products or proteins. Individual proteins can be prepared by expression of cloned cDNAs, the sequences of which are complementary to that of mRNA. Therefore, cDNAs that encode the full length of the open reading frames (ORFs) are essential resources for both functional genomics and the search for drug target molecules. We have compiled full-length human cDNA libraries, and in the process identi®ed some promising drug targets from the libraries and human genome sequences. Current genomic drug discovery starts with the identi®cation of candidate genes or molecules, followed by the elucidation of their biological activities and functions, and screening of the compounds with assay systems. The leading compounds are evaluated in animal pharmacology and toxicology studies. Because the direction of genomic drug discovery runs counter to that of conventional pharmacology, it was termed `reverse pharmacology on a genome scale.