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  1. Article ; Online: Inverse Mixed-Solvent Molecular Dynamics for Visualization of the Residue Interaction Profile of Molecular Probes

    Keisuke Yanagisawa / Ryunosuke Yoshino / Genki Kudo / Takatsugu Hirokawa

    International Journal of Molecular Sciences, Vol 23, Iss 4749, p

    2022  Volume 4749

    Abstract: To ensure efficiency in discovery and development, the application of computational technology is essential. Although virtual screening techniques are widely applied in the early stages of drug discovery research, the computational methods used in lead ... ...

    Abstract To ensure efficiency in discovery and development, the application of computational technology is essential. Although virtual screening techniques are widely applied in the early stages of drug discovery research, the computational methods used in lead optimization to improve activity and reduce the toxicity of compounds are still evolving. In this study, we propose a method to construct the residue interaction profile of the chemical structure used in the lead optimization by performing “inverse” mixed-solvent molecular dynamics (MSMD) simulation. Contrary to constructing a protein-based, atom interaction profile, we constructed a probe-based, protein residue interaction profile using MSMD trajectories. It provides us the profile of the preferred protein environments of probes without co-crystallized structures. We assessed the method using three probes: benzamidine, catechol, and benzene. As a result, the residue interaction profile of each probe obtained by MSMD was a reasonable physicochemical description of the general non-covalent interaction. Moreover, comparison with the X-ray structure containing each probe as a ligand shows that the map of the interaction profile matches the arrangement of amino acid residues in the X-ray structure.
    Keywords mixed-solvent molecular dynamics ; interaction pattern analysis ; residue interaction profile ; visualization ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 541
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Book ; Online: Identification of Key Interactions Between SARS-CoV-2 Main Protease and Inhibitor Drug Candidates

    Ryunosuke Yoshino / Nobuaki Yasuo / Masakazu Sekijima

    2020  

    Abstract: The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been reported that ...

    Abstract The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been reported that peptide-like anti-HIV-1 drugs are effective against SARS-CoV Main protease (M pro ). Due to the close phylogenetic relationship between SARS-CoV and SARS-CoV-2, their main proteases share many structural and functional features. Thus, these drugs are also regarded as potential drug candidates targeting SARS-CoV-2 M pro . However, the mechanism of action of SARS-CoV-2 M pro at the atomic-level is unknown. In the present study, we revealed key interactions between SARS-CoV-2 M pro and three drug candidates by performing pharmacophore modeling and 1μs molecular dynamics (MD) simulations. His41, Gly143, and Glu166 formed interactions with the functional groups that were common among peptide-like inhibitors in all MD simulations. These interactions are important targets for potential drugs against SARS-CoV-2 M pro .
    Keywords Bioinformatics and Computational Biology ; Biophysics ; Computational Chemistry and Modeling ; Biophysical Chemistry ; COVID-19 ; SARS-CoV-2 ; main protease ; interaction analysis ; molecular dynamics ; pharmacophore model ; covid19
    Subject code 333
    Publishing date 2020-03-23T12:27:21Z
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Identification of key interactions between SARS-CoV-2 main protease and inhibitor drug candidates

    Ryunosuke Yoshino / Nobuaki Yasuo / Masakazu Sekijima

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 8

    Abstract: Abstract The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been ... ...

    Abstract Abstract The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been reported that peptide-like anti-HIV-1 drugs are effective against SARS-CoV Main protease (Mpro). Due to the close phylogenetic relationship between SARS-CoV and SARS-CoV-2, their main proteases share many structural and functional features. Thus, these drugs are also regarded as potential drug candidates targeting SARS-CoV-2 Mpro. However, the mechanism of action of SARS-CoV-2 Mpro at the atomic-level is unknown. In the present study, we revealed key interactions between SARS-CoV-2 Mpro and three drug candidates by performing pharmacophore modeling and 1 μs molecular dynamics (MD) simulations. His41, Gly143, and Glu166 formed interactions with the functional groups that were common among peptide-like inhibitors in all MD simulations. These interactions are important targets for potential drugs against SARS-CoV-2 Mpro.
    Keywords Medicine ; R ; Science ; Q ; covid19
    Subject code 572
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Molecular Dynamics Simulation reveals the mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance against Baloxavir marboxil

    Ryunosuke Yoshino / Nobuaki Yasuo / Masakazu Sekijima

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 8

    Abstract: Abstract Baloxavir marboxil (BXM), an antiviral drug for influenza virus, inhibits RNA replication by binding to RNA replication cap-dependent endonuclease (CEN) of influenza A and B viruses. Although this drug was only approved by the FDA in October ... ...

    Abstract Abstract Baloxavir marboxil (BXM), an antiviral drug for influenza virus, inhibits RNA replication by binding to RNA replication cap-dependent endonuclease (CEN) of influenza A and B viruses. Although this drug was only approved by the FDA in October 2018, drug resistant viruses have already been detected from clinical trials owing to an I38 mutation of CEN. To investigate the reduction of drug sensitivity by the I38 mutant variants, we performed a molecular dynamics (MD) simulation on the CEN-BXM complex structure to analyze variations in the mode of interaction. Our simulation results suggest that the side chain methyl group of I38 in CEN engages in a CH-pi interaction with the aromatic ring of BXM. This interaction is abolished in various I38 mutant variants. Moreover, MD simulation on various mutation models and binding free energy prediction by MM/GBSA method suggest that the I38 mutation precludes any interaction with the aromatic ring of BXA and thereby reduces BXA sensitivity.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis

    Motohiro Sekiya / Kenta Kainoh / Takehito Sugasawa / Ryunosuke Yoshino / Takatsugu Hirokawa / Hiroaki Tokiwa / Shogo Nakano / Satoru Nagatoishi / Kouhei Tsumoto / Yoshinori Takeuchi / Takafumi Miyamoto / Takashi Matsuzaka / Hitoshi Shimano

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 19

    Abstract: Sensing of nutrient status coordinates the regulation of liver glucose and lipid metabolism, and is important for metabolic homeostasis. Here the authors report that transcriptional the corepressor CtBP2 can sense nutrient status and coordinate ... ...

    Abstract Sensing of nutrient status coordinates the regulation of liver glucose and lipid metabolism, and is important for metabolic homeostasis. Here the authors report that transcriptional the corepressor CtBP2 can sense nutrient status and coordinate repression of liver glucose and lipid metabolism via Fox01 and SREBP1, respectively.
    Keywords Science ; Q
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Molecular action of larvicidal flavonoids on ecdysteroidogenic glutathione S-transferase Noppera-bo in Aedes aegypti

    Kazue Inaba / Kana Ebihara / Miki Senda / Ryunosuke Yoshino / Chisako Sakuma / Kotaro Koiwai / Daisuke Takaya / Chiduru Watanabe / Akira Watanabe / Yusuke Kawashima / Kaori Fukuzawa / Riyo Imamura / Hirotatsu Kojima / Takayoshi Okabe / Nozomi Uemura / Shinji Kasai / Hirotaka Kanuka / Takashi Nishimura / Kodai Watanabe /
    Hideshi Inoue / Yuuta Fujikawa / Teruki Honma / Takatsugu Hirokawa / Toshiya Senda / Ryusuke Niwa

    BMC Biology, Vol 20, Iss 1, Pp 1-

    2022  Volume 20

    Abstract: Abstract Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of ... ...

    Abstract Abstract Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment. However, the mode of mosquito larvicidal action of flavonoids has not been elucidated. Results Here, we report that several flavonoids, including daidzein, inhibit the activity of glutathione S-transferase Noppera-bo (Nobo), an enzyme used for the biosynthesis of the insect steroid hormone ecdysone, in the yellow fever mosquito Aedes aegypti. The crystal structure of the Nobo protein of Ae. aegypti (AeNobo) complexed with the flavonoids and its molecular dynamics simulation revealed that Glu113 forms a hydrogen bond with the flavonoid inhibitors. Consistent with this observation, substitution of Glu113 with Ala drastically reduced the inhibitory activity of the flavonoids against AeNobo. Among the identified flavonoid-type inhibitors, desmethylglycitein (4′,6,7-trihydroxyisoflavone) exhibited the highest inhibitory activity in vitro. Moreover, the inhibitory activities of the flavonoids correlated with the larvicidal activity, as desmethylglycitein suppressed Ae. aegypti larval development more efficiently than daidzein. Conclusion Our study demonstrates the mode of action of flavonoids on the Ae. aegypti Nobo protein at the atomic, enzymatic, and organismal levels.
    Keywords Aedes aegypti ; Ecdysone ; Ecdysteroid ; Flavonoid ; Glutathione S-transferase ; Insect growth regulator ; Biology (General) ; QH301-705.5
    Subject code 500
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease

    Ryunosuke Yoshino / Nobuaki Yasuo / Yohsuke Hagiwara / Takashi Ishida / Daniel Ken Inaoka / Yasushi Amano / Yukihiro Tateishi / Kazuki Ohno / Ichiji Namatame / Tatsuya Niimi / Masaya Orita / Kiyoshi Kita / Yutaka Akiyama / Masakazu Sekijima

    Scientific Reports, Vol 7, Iss 1, Pp 1-

    2017  Volume 9

    Abstract: Abstract Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness ... ...

    Abstract Abstract Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer “TSUBAME2.5” and conducted in vitro enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit T. cruzi SpdSyn (TcSpdSyn) by in silico and in vitro screening. We also determined the TcSpdSyn–hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.
    Keywords Medicine ; R ; 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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  8. Article ; Online: Pharmacophore modeling for anti-Chagas drug design using the fragment molecular orbital method.

    Ryunosuke Yoshino / Nobuaki Yasuo / Daniel Ken Inaoka / Yohsuke Hagiwara / Kazuki Ohno / Masaya Orita / Masayuki Inoue / Tomoo Shiba / Shigeharu Harada / Teruki Honma / Emmanuel Oluwadare Balogun / Josmar Rodrigues da Rocha / Carlos Alberto Montanari / Kiyoshi Kita / Masakazu Sekijima

    PLoS ONE, Vol 10, Iss 5, p e

    2015  Volume 0125829

    Abstract: Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that causes severe human health problems. To develop a new chemotherapeutic agent for the treatment of Chagas disease, we predicted a pharmacophore model for T. ... ...

    Abstract Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that causes severe human health problems. To develop a new chemotherapeutic agent for the treatment of Chagas disease, we predicted a pharmacophore model for T. cruzi dihydroorotate dehydrogenase (TcDHODH) by fragment molecular orbital (FMO) calculation for orotate, oxonate, and 43 orotate derivatives.Intermolecular interactions in the complexes of TcDHODH with orotate, oxonate, and 43 orotate derivatives were analyzed by FMO calculation at the MP2/6-31G level. The results indicated that the orotate moiety, which is the base fragment of these compounds, interacts with the Lys43, Asn67, and Asn194 residues of TcDHODH and the cofactor flavin mononucleotide (FMN), whereas functional groups introduced at the orotate 5-position strongly interact with the Lys214 residue.FMO-based interaction energy analyses revealed a pharmacophore model for TcDHODH inhibitor. Hydrogen bond acceptor pharmacophores correspond to Lys43 and Lys214, hydrogen bond donor and acceptor pharmacophores correspond to Asn67 and Asn194, and the aromatic ring pharmacophore corresponds to FMN, which shows important characteristics of compounds that inhibit TcDHODH. In addition, the Lys214 residue is not conserved between TcDHODH and human DHODH. Our analysis suggests that these orotate derivatives should preferentially bind to TcDHODH, increasing their selectivity. Our results obtained by pharmacophore modeling provides insight into the structural requirements for the design of TcDHODH inhibitors and their development as new anti-Chagas drugs.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: A prospective compound screening contest identified broader inhibitors for Sirtuin 1

    Shuntaro Chiba / Masahito Ohue / Anastasiia Gryniukova / Petro Borysko / Sergey Zozulya / Nobuaki Yasuo / Ryunosuke Yoshino / Kazuyoshi Ikeda / Woong-Hee Shin / Daisuke Kihara / Mitsuo Iwadate / Hideaki Umeyama / Takaaki Ichikawa / Reiji Teramoto / Kun-Yi Hsin / Vipul Gupta / Hiroaki Kitano / Mika Sakamoto / Akiko Higuchi /
    Nobuaki Miura / Kei Yura / Masahiro Mochizuki / Chandrasekaran Ramakrishnan / A. Mary Thangakani / D. Velmurugan / M. Michael Gromiha / Itsuo Nakane / Nanako Uchida / Hayase Hakariya / Modong Tan / Hironori K. Nakamura / Shogo D. Suzuki / Tomoki Ito / Masahiro Kawatani / Kentaroh Kudoh / Sakurako Takashina / Kazuki Z. Yamamoto / Yoshitaka Moriwaki / Keita Oda / Daisuke Kobayashi / Tatsuya Okuno / Shintaro Minami / George Chikenji / Philip Prathipati / Chioko Nagao / Attayeb Mohsen / Mari Ito / Kenji Mizuguchi / Teruki Honma / Takashi Ishida / Takatsugu Hirokawa / Yutaka Akiyama / Masakazu Sekijima

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: Abstract Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library ... ...

    Abstract Abstract Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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