Laboratory of Drug Design and Medicinal Chemistry

Staff

Toshimasa Itoh, Ph.D.Professor

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Hiroaki Ishida, Ph.D.Senior Assistant Professor

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Nami Ohashi, Ph.D.Senior Assistant Professor

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Takahiro Yamada, Ph.D.Assistant Professor

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Message

The life phenomenon is supported by a lot of chemical reactions. We are aiming to clarify the life phenomenon at a molecular level by using the techniques of chemistry and biology. We are now studying the structure based drug design and the synthesis of the medicines targeting proteins such as receptors and enzymes.

Research themes

  1. Discovery of nuclear receptor ligands
  2. Design and synthesis of drugs treating metabolic syndromes
  3. Molecular mechanism of gene transcription by nuclear receptors
  4. Asymmetric syntheses of seed compounds for medicines

Research perspectives

Vitamin D and Vitamin D receptor

1α, 25-Dihydroxyvitamin D 3 is an active form of vitamin D and plays essential roles incalcium homeostasis, cell differentiation and proliferation, and immunology. It exertsactions through gene transcription by binding to vitamin D receptor (VDR) belonging tothe nuclear receptor superfamily. VDR changes its conformation to an active form from aninactive form by binding 1α, 25-Dihydroxyvitamin D 3 as well as various agonists (vitaminD analogues). On binding, VDR forms a heterodimer with retinoid X receptor (RXR).Then, the RXR−VDR heterodimer on response element of the target gene recruits thecoactivator and transcripts the target gene.

Various vitamin D analogues have been developed by many groups in the world, since1α, 25-Dihydroxyvitamin D 3 is pharmaceutically important. In fact, VDR agonists areclinically used to treat metabolic bone diseases and skin diseases such as psoriasis.

Under such a background, we designed and synthesized vitamin D analogues basedon the pocket structure of vitamin D receptor. Analogues showed agonistic, partialagonistic or antagonistic activity dependent on each analogue structure. To investigatethe mechanism of characteristic behaviors of each analogue, we are continuing the studyof interactions between the receptor and analogues using structural biological techniques,such as X-ray crystallography, Bio-SAXS, ESI-mass spectrometry, and so on.

Polyunsaturated fatty acid and its target protein

It is known that metabolites of polyunsaturated fatty acids (PUFAs) are involved inimportant physiological role. Because of its potency, one of our interests is omega-3PUFAs and those derivatives.

In previous study, we designed and synthesized 4-oxoDHA as targeting PPARγ thatshowed transcriptional activity and improved blood glucose level in vivo experiments. Inaddition, it revealed that 4-oxoDHA covalently modified PPARγ.

To contribute drug discovery, one of our researches is design and synthesis of PUFAderivatives that target metabolic syndrome related molecules. Furthermore the syntheticfatty acids were used as probe to understand how PUFA regulate the target proteinsapplying biophysical techniques including X-ray crystallography and mass spectroscopy.

Laboratory

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Showa Pharmaceutical University

3-3165 Higashi-Tamagawagakuen,
Machidashi,Tokyo 194-8543, Japan
TEL +81-42-721-1511

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