平野　秀典 （ヒラノ　ヨシノリ）

Hirano, Toshinori

写真a

所属（所属キャンパス）

理工学研究科 （矢上）

職名

特任准教授（有期）

外部リンク
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学歴 【 表示 ／ 非表示 】

  • 1997年03月

    明治薬科大学, 薬学部, 製薬学科

    大学, 卒業

  • 2002年03月

    千葉大学, 薬学研究科, 総合薬品科学専攻

    大学院, 修了, 博士

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 薬系分析、物理化学 （Physical Pharmaceutical Science）

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論文 【 表示 ／ 非表示 】

  • Bisabosqual A: A novel asparagine synthetase inhibitor suppressing the proliferation and migration of human non-small cell lung cancer A549 cells

    Pan Y., Suzuki T., Sakai K., Hirano Y., Ikeda H., Hattori A., Dohmae N., Nishio K., Kakeya H.

    European Journal of Pharmacology （European Journal of Pharmacology）  960 2023年12月

    ISSN  00142999

    　概要を見る

    Asparagine synthetase (ASNS) is a crucial enzyme for the de novo biosynthesis of endogenous asparagine (Asn), and ASNS shows the positive relationship with the growth of several solid tumors. Most of ASNS inhibitors are analogs of transition-state in ASNS reaction, but their low cell permeability hinders their anticancer activity. Therefore, novel ASNS inhibitors with a new pharmacophore urgently need to be developed. In this study, we established and applied a system for in vitro screening of ASNS inhibitors, and found a promising unique bisabolane-type meroterpenoid molecule, bisabosqual A (Bis A), able to covalently modify K556 site of ASNS protein. Bis A targeted ASNS to suppress cell proliferation of human non-small cell lung cancer A549 cells and exhibited a synergistic effect with L-asparaginase (L-ASNase). Mechanistically, Bis A promoted oxidative stress and apoptosis, while inhibiting autophagy, cell migration and epithelial-mesenchymal transition (EMT), impeding cancer cell development. Moreover, Bis A induced negative feedback pathways containing the GCN2-eIF2α-ATF4, PI3K-AKT-mTORC1 and RAF-MEK-ERK axes, but combination treatment of Bis A and rapamycin/torin-1 overcame the potential drug resistance triggered by mTOR pathways. Our study demonstrates that ASNS inhibition is promising for cancer chemotherapy, and Bis A is a potential lead ASNS inhibitor for anticancer development.

  • Effect of temperature on the structure and drug-release behaviour of inclusion complex of β-cyclodextrin with cyclophosphamide: a molecular dynamics study

    Sakai S., Hirano Y., Kobayashi Y., Arai N.

    Soft Matter （Soft Matter）  19 （ 16 ） 2902 - 2907 2023年03月

    ISSN  1744683X

    　概要を見る

    Cyclodextrins (CDs) are suitable drug carriers because of their doughnut-shaped cavities with hydrophilic outer and hydrophobic inner surfaces. Temperature-responsive CD-based drug carriers are expected to be one of the most promising candidates for drug delivery systems. In this study, we performed molecular dynamics simulations of the inclusion complex of β-CD with cyclophosphamide (CP) at temperatures from 300 K to 400 K to investigate the temperature dependency of the release behaviour of CP and structural changes of β-CD in an aqueous solution. We analysed the distance between the centres of mass of β-CD and CP and the radius of gyration of β-CD. The CP molecule was released from the β-CD cavity at 400 K, whereas two different inclusion complexes, partially and completely, were observed at T < 400 K. β-CD encapsulating a CP molecule had a more spherical shape and rigidity than β-CD without a CP, and the rigidity of their inclusion complex decreased with increasing temperature. Our findings provide fundamental insights into the behaviours of the β-CD/CP complex and drug release at the molecular level and can facilitate the development of new temperature-responsive drug delivery systems with CD nanocarriers triggered by localised temperature increases using focused ultrasound.

  • Wetting hysteresis induces effective unidirectional water transport through a fluctuating nanochannel

    Arai N., Yamamoto E., Koishi T., Hirano Y., Yasuoka K., Ebisuzaki T.

    Nanoscale Horizons （Nanoscale Horizons）  8 （ 5 ） 652 - 661 2023年02月

    ISSN  20556756

    　概要を見る

    We propose a water pump that actively transports water molecules through nanochannels. Spatially asymmetric noise fluctuations imposed on the channel radius cause unidirectional water flow without osmotic pressure, which can be attributed to hysteresis in the cyclic transition between the wetting/drying states. We show that the water transport depends on fluctuations, such as white, Brownian, and pink noises. Because of the high-frequency components in white noise, fast switching of open and closed states inhibits channel wetting. Conversely, pink and Brownian noises generate high-pass filtered net flow. Brownian fluctuation leads to a faster water transport rate, whereas pink noise has a higher capability to overcome pressure differences in the opposite direction. A trade-off relationship exists between the resonant frequency of the fluctuation and the flow amplification. The proposed pump can be considered as an analogy for the reversed Carnot cycle, which is the upper limit of the energy conversion efficiency.

  • Differences in ligand-induced protein dynamics extracted from an unsupervised deep learning approach correlate with protein–ligand binding affinities

    Yasuda I., Endo K., Yamamoto E., Hirano Y., Yasuoka K.

    Communications Biology （Communications Biology）  5 （ 1 ）  2022年12月

    　概要を見る

    Prediction of protein–ligand binding affinity is a major goal in drug discovery. Generally, free energy gap is calculated between two states (e.g., ligand binding and unbinding). The energy gap implicitly includes the effects of changes in protein dynamics induced by ligand binding. However, the relationship between protein dynamics and binding affinity remains unclear. Here, we propose a method that represents ligand-binding-induced protein behavioral change with a simple feature that can be used to predict protein–ligand affinity. From unbiased molecular simulation data, an unsupervised deep learning method measures the differences in protein dynamics at a ligand-binding site depending on the bound ligands. A dimension reduction method extracts a dynamic feature that strongly correlates to the binding affinities. Moreover, the residues that play important roles in protein–ligand interactions are specified based on their contribution to the differences. These results indicate the potential for binding dynamics-based drug discovery.

  • Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding

    Hirano Y., Okimoto N., Fujita S., Taiji M.

    ACS Omega （ACS Omega）  6 （ 27 ） 17609 - 17620 2021年

    　概要を見る

    The interactions between proteins and ligands are involved in various biological functions. While experimental structures provide key static structural information of ligand-unbound and ligand-bound proteins, dynamic information is often insufficient for understanding the detailed mechanism of protein-ligand binding. Here, we studied the conformational changes of the tankyrase 2 binding pocket upon ligand binding using molecular dynamics simulations of the ligand-unbound and ligand-bound proteins. The ligand-binding pocket has two subsites: The nicotinamide and adenosine subsite. Comparative analysis of these molecular dynamics trajectories revealed that the conformational change of the ligand-binding pocket was characterized by four distinct conformations of the ligand-binding pocket. Two of the four conformations were observed only in molecular dynamics simulations. We found that the pocket conformational change on ligand binding was based on the connection between the nicotinamide and adenosine subsites that are located adjacently in the pocket. From the analysis, we proposed the protein-ligand binding mechanism of tankyrase 2. Finally, we discussed the computational prediction of the ligand binding pose using the tankyrase 2 structures obtained from the molecular dynamics simulations.

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担当授業科目 【 表示 ／ 非表示 】

  • 看護のための薬理学

    2024年度

  • 看護のための薬理学

    2023年度

  • 看護のための薬理学

    2022年度

  • 看護のための薬理学

    2021年度

  • 看護のための薬理学

    2020年度

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