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  1. Article ; Online: AI-driven molecular generation of not-patented pharmaceutical compounds using world open patent data

    Yugo Shimizu / Masateru Ohta / Shoichi Ishida / Kei Terayama / Masanori Osawa / Teruki Honma / Kazuyoshi Ikeda

    Journal of Cheminformatics, Vol 15, Iss 1, Pp 1-

    2023  Volume 11

    Abstract: Abstract Developing compounds with novel structures is important for the production of new drugs. From an intellectual perspective, confirming the patent status of newly developed compounds is essential, particularly for pharmaceutical companies. The ... ...

    Abstract Abstract Developing compounds with novel structures is important for the production of new drugs. From an intellectual perspective, confirming the patent status of newly developed compounds is essential, particularly for pharmaceutical companies. The generation of a large number of compounds has been made possible because of the recent advances in artificial intelligence (AI). However, confirming the patent status of these generated molecules has been a challenge because there are no free and easy-to-use tools that can be used to determine the novelty of the generated compounds in terms of patents in a timely manner; additionally, there are no appropriate reference databases for pharmaceutical patents in the world. In this study, two public databases, SureChEMBL and Google Patents Public Datasets, were used to create a reference database of drug-related patented compounds using international patent classification. An exact structure search system was constructed using InChIKey and a relational database system to rapidly search for compounds in the reference database. Because drug-related patented compounds are a good source for generative AI to learn useful chemical structures, they were used as the training data. Furthermore, molecule generation was successfully directed by increasing and decreasing the number of generated patented compounds through incorporation of patent status (i.e., patented or not) into learning. The use of patent status enabled generation of novel molecules with high drug-likeness. The generation using generative AI with patent information would help efficiently propose novel compounds in terms of pharmaceutical patents. Scientific contribution: In this study, a new molecule-generation method that takes into account the patent status of molecules, which has rarely been considered but is an important feature in drug discovery, was developed. The method enables the generation of novel molecules based on pharmaceutical patents with high drug-likeness and will help in the efficient ...
    Keywords Patented compounds ; Drug discovery ; Database ; Compound search ; Molecular generation ; Reward function ; Information technology ; T58.5-58.64 ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Identification of novel inhibitors of Keap1/Nrf2 by a promising method combining protein–protein interaction-oriented library and machine learning

    Yugo Shimizu / Tomoki Yonezawa / Junichi Sakamoto / Toshio Furuya / Masanori Osawa / Kazuyoshi Ikeda

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 13

    Abstract: Abstract Protein–protein interactions (PPIs) are prospective but challenging targets for drug discovery, because screening using traditional small-molecule libraries often fails to identify hits. Recently, we developed a PPI-oriented library comprising ... ...

    Abstract Abstract Protein–protein interactions (PPIs) are prospective but challenging targets for drug discovery, because screening using traditional small-molecule libraries often fails to identify hits. Recently, we developed a PPI-oriented library comprising 12,593 small-to-medium-sized newly synthesized molecules. This study validates a promising combined method using PPI-oriented library and ligand-based virtual screening (LBVS) to discover novel PPI inhibitory compounds for Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2). We performed LBVS with two random forest models against our PPI library and the following time-resolved fluorescence resonance energy transfer (TR-FRET) assays of 620 compounds identified 15 specific hit compounds. The high hit rates for the entire PPI library (estimated 0.56–1.3%) and the LBVS (maximum 5.4%) compared to a conventional screening library showed the utility of the library and the efficiency of LBVS. All the hit compounds possessed novel structures with Tanimoto similarity ≤ 0.26 to known Keap1/Nrf2 inhibitors and aqueous solubility (AlogP < 5). Reasonable binding modes were predicted using 3D alignment of five hit compounds and a Keap1/Nrf2 peptide crystal structure. Our results represent a new, efficient method combining the PPI library and LBVS to identify novel PPI inhibitory ligands with expanded chemical space.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Conformational equilibrium shift underlies altered K+ channel gating as revealed by NMR

    Yuta Iwahashi / Yuki Toyama / Shunsuke Imai / Hiroaki Itoh / Masanori Osawa / Masayuki Inoue / Ichio Shimada

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 11

    Abstract: Potassium ion channels control K+ permeation across cell membranes and mutations that cause cardiovascular and neural diseases are known. Here, the authors perform NMR measurements with the prototypical K+ channel from Streptomyces lividans, KcsA and ... ...

    Abstract Potassium ion channels control K+ permeation across cell membranes and mutations that cause cardiovascular and neural diseases are known. Here, the authors perform NMR measurements with the prototypical K+ channel from Streptomyces lividans, KcsA and characterise the effects of disease causing mutations on the conformational dynamics of K+ channels in a physiological solution environment.
    Keywords Science ; Q
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel

    Hanaho Kano / Yuki Toyama / Shunsuke Imai / Yuta Iwahashi / Yoko Mase / Mariko Yokogawa / Masanori Osawa / Ichio Shimada

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 13

    Abstract: Opening of G protein-gated inwardly rectifying potassium channels (GIRK) is coupled to the activation of a GPCR. Here the authors use NMR and cell-based BRET assays to gain insights into the mechanisms underlying family-specific activation and find that ... ...

    Abstract Opening of G protein-gated inwardly rectifying potassium channels (GIRK) is coupled to the activation of a GPCR. Here the authors use NMR and cell-based BRET assays to gain insights into the mechanisms underlying family-specific activation and find that pre-formation of the Gαi/oβγ-GIRK complex in the inactive state is responsible for specific GIRK activation and present a structural model for the Gαi/oβγ-GIRK complex.
    Keywords Science ; Q
    Language English
    Publishing date 2019-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel

    Hanaho Kano / Yuki Toyama / Shunsuke Imai / Yuta Iwahashi / Yoko Mase / Mariko Yokogawa / Masanori Osawa / Ichio Shimada

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 13

    Abstract: Opening of G protein-gated inwardly rectifying potassium channels (GIRK) is coupled to the activation of a GPCR. Here the authors use NMR and cell-based BRET assays to gain insights into the mechanisms underlying family-specific activation and find that ... ...

    Abstract Opening of G protein-gated inwardly rectifying potassium channels (GIRK) is coupled to the activation of a GPCR. Here the authors use NMR and cell-based BRET assays to gain insights into the mechanisms underlying family-specific activation and find that pre-formation of the Gαi/oβγ-GIRK complex in the inactive state is responsible for specific GIRK activation and present a structural model for the Gαi/oβγ-GIRK complex.
    Keywords Science ; Q
    Language English
    Publishing date 2019-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Dynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses

    Yuki Toyama / Hanaho Kano / Yoko Mase / Mariko Yokogawa / Masanori Osawa / Ichio Shimada

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 15

    Abstract: Heterotrimeric guanine-nucleotide-binding proteins (G proteins) act as molecular switches. Here the authors use NMR relaxation analyses, which reveal the dynamics of G protein alpha subunit binding to GDP on a microsecond timescale. ...

    Abstract Heterotrimeric guanine-nucleotide-binding proteins (G proteins) act as molecular switches. Here the authors use NMR relaxation analyses, which reveal the dynamics of G protein alpha subunit binding to GDP on a microsecond timescale.
    Keywords Science ; Q
    Language English
    Publishing date 2017-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Characterization of the multimeric structure of poly(A)-binding protein on a poly(A) tail

    Ryoichi Sawazaki / Shunsuke Imai / Mariko Yokogawa / Nao Hosoda / Shin-ichi Hoshino / Muneyo Mio / Kazuhiro Mio / Ichio Shimada / Masanori Osawa

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Abstract Eukaryotic mature mRNAs possess a poly adenylate tail (poly(A)), to which multiple molecules of poly(A)-binding protein C1 (PABPC1) bind. PABPC1 regulates translation and mRNA metabolism by binding to regulatory proteins. To understand ... ...

    Abstract Abstract Eukaryotic mature mRNAs possess a poly adenylate tail (poly(A)), to which multiple molecules of poly(A)-binding protein C1 (PABPC1) bind. PABPC1 regulates translation and mRNA metabolism by binding to regulatory proteins. To understand functional mechanism of the regulatory proteins, it is necessary to reveal how multiple molecules of PABPC1 exist on poly(A). Here, we characterize the structure of the multiple molecules of PABPC1 on poly(A), by using transmission electron microscopy (TEM), chemical cross-linking, and NMR spectroscopy. The TEM images and chemical cross-linking results indicate that multiple PABPC1 molecules form a wormlike structure in the PABPC1-poly(A) complex, in which the PABPC1 molecules are linearly arrayed. NMR and cross-linking analyses indicate that PABPC1 forms a multimer by binding to the neighbouring PABPC1 molecules via interactions between the RNA recognition motif (RRM) 2 in one molecule and the middle portion of the linker region of another molecule. A PABPC1 mutant lacking the interaction site in the linker, which possesses an impaired ability to form the multimer, reduced the in vitro translation activity, suggesting the importance of PABPC1 multimer formation in the translation process. We therefore propose a model of the PABPC1 multimer that provides clues to comprehensively understand the regulation mechanism of mRNA translation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Functional roles of Mg2+ binding sites in ion-dependent gating of a Mg2+ channel, MgtE, revealed by solution NMR

    Tatsuro Maruyama / Shunsuke Imai / Tsukasa Kusakizako / Motoyuki Hattori / Ryuichiro Ishitani / Osamu Nureki / Koichi Ito / Andrès D Maturana / Ichio Shimada / Masanori Osawa

    eLife, Vol

    2018  Volume 7

    Abstract: Magnesium ions (Mg2+) are divalent cations essential for various cellular functions. Mg2+ homeostasis is maintained through Mg2+ channels such as MgtE, a prokaryotic Mg2+ channel whose gating is regulated by intracellular Mg2+ levels. Our previous ... ...

    Abstract Magnesium ions (Mg2+) are divalent cations essential for various cellular functions. Mg2+ homeostasis is maintained through Mg2+ channels such as MgtE, a prokaryotic Mg2+ channel whose gating is regulated by intracellular Mg2+ levels. Our previous crystal structure of MgtE in the Mg2+-bound, closed state revealed the existence of seven crystallographically-independent Mg2+-binding sites, Mg1–Mg7. The role of Mg2+-binding to each site in channel closure remains unknown. Here, we investigated Mg2+-dependent changes in the structure and dynamics of MgtE using nuclear magnetic resonance spectroscopy. Mg2+-titration experiments, using wild-type and mutant forms of MgtE, revealed that the Mg2+ binding sites Mg1, Mg2, Mg3, and Mg6, exhibited cooperativity and a higher affinity for Mg2+, enabling the remaining Mg2+ binding sites, Mg4, Mg5, and Mg7, to play important roles in channel closure. This study revealed the role of each Mg2+-binding site in MgtE gating, underlying the mechanism of cellular Mg2+ homeostasis.
    Keywords Mg2+ homeostasis ; Mg2+ channel ; MgtE ; gating mechanism ; NMR ; thermus thermophiles ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: ATP-dependent modulation of MgtE in Mg2+ homeostasis

    Atsuhiro Tomita / Mingfeng Zhang / Fei Jin / Wenhui Zhuang / Hironori Takeda / Tatsuro Maruyama / Masanori Osawa / Ken-ichi Hashimoto / Hisashi Kawasaki / Koichi Ito / Naoshi Dohmae / Ryuichiro Ishitani / Ichio Shimada / Zhiqiang Yan / Motoyuki Hattori / Osamu Nureki

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 11

    Abstract: Author summary MgtE is an Mg2+ transporter involved in Mg2+ homeostasis. Here, the authors report that ATP regulates the Mg+2-dependent gating of MgtE and use X-ray crystallography combined with functional studies to propose the molecular mechanisms ... ...

    Abstract Author summary MgtE is an Mg2+ transporter involved in Mg2+ homeostasis. Here, the authors report that ATP regulates the Mg+2-dependent gating of MgtE and use X-ray crystallography combined with functional studies to propose the molecular mechanisms involved in this process.
    Keywords Science ; Q
    Language English
    Publishing date 2017-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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