構造生物 Vol.4 No.2
1998年8月発行

Expectation to Structural Biology for Innovative Drug Discovery


Tadao Shibanuma

Yamanouchi Pharmaceutical Co.,Ltd. Institute for Drug Discovery

Worldwide huge investment is now being made by a large number of companies with expectation of new drug discovery using genomics for the 21st century. Although a lot of information for gene is accumulated, function analysis still seems to be a problem to be overcome.

Bioinformatics and chemoinformatics are very important for drug discovery process. As for bioinformatics, construction of systematic database is required in order to roughly predict what family the protein belongs to and what function it has by homology search using amino acid sequences. Based on these information, following steps are necessary for innovative drug discovery : identifying the disease to which that protein plays an important role at cell level by physiological experiments, analysing the function of the protein with technologies using antisense or knockout mouse, constructing the assay system, searching small molecular compounds and evaluation of the compound with the appropriate animal model developed for the disease.

At this stage, if the three dimensional structure of homologous protein is determined, hopefully in complex with its ligand, by NMR spectroscopy or X-ray crystallography, it would be possible to predict the active site of the target protein using the structure of the homologous one as a template. For example, in the case of enzymes, whose structures have been extensively studied so far, a lot of tyrosine kinases and serine/threonine kinases are involved in the signal trunsduction. It is the first entrance to the drug discovery study to examine the role of each enzyme in signal transduction and to obtain the selective inhibitor. For the discovery of the selective inhibitor, the three dimensional structure of the enzyme and its relation to the substrate and the selective inhibitor are very useful. We thus hope the rapid increase in the determinataion of three dimensional structure of target proteins.

Moreover, in terms of drug discovery there are a lot of targets other than enzymes such as interaction between transcription factors and DNA, the mechanism of ion channel, the binding of ligand to its receptor and protein-pretein interactions (including SH2, SH3 domain etc.). The structure analysis of these targets as well as the function analysis would be the most fantastic and promising projects in the 21st century. We hope that structural biology would be further advanced and the establishments of scientific aspects for the drug discovery would accelerate the process. TARA projects involving company people would probably make large contributions to the development of structural biology.


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sasaki@tara.met.nagoya-u.ac.jp