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  1. Article ; Online: MERMAID

    Daiki Erikawa / Nobuaki Yasuo / Masakazu Sekijima

    Journal of Cheminformatics, Vol 13, Iss 1, Pp 1-

    an open source automated hit-to-lead method based on deep reinforcement learning

    2021  Volume 10

    Abstract: Abstract The hit-to-lead process makes the physicochemical properties of the hit molecules that show the desired type of activity obtained in the screening assay more drug-like. Deep learning-based molecular generative models are expected to contribute ... ...

    Abstract Abstract The hit-to-lead process makes the physicochemical properties of the hit molecules that show the desired type of activity obtained in the screening assay more drug-like. Deep learning-based molecular generative models are expected to contribute to the hit-to-lead process. The simplified molecular input line entry system (SMILES), which is a string of alphanumeric characters representing the chemical structure of a molecule, is one of the most commonly used representations of molecules, and molecular generative models based on SMILES have achieved significant success. However, in contrast to molecular graphs, during the process of generation, SMILES are not considered as valid SMILES. Further, it is quite difficult to generate molecules starting from a certain molecule, thus making it difficult to apply SMILES to the hit-to-lead process. In this study, we have developed a SMILES-based generative model that can be generated starting from a certain molecule. This method generates partial SMILES and inserts it into the original SMILES using Monte Carlo Tree Search and a Recurrent Neural Network. We validated our method using a molecule dataset obtained from the ZINC database and successfully generated molecules that were both well optimized for the objectives of the quantitative estimate of drug-likeness (QED) and penalized octanol-water partition coefficient (PLogP) optimization. The source code is available at https://github.com/sekijima-lab/mermaid .
    Keywords Molecular generation ; Lead Optimization ; Hit-to-Lead ; Monte Carlo Tree Search ; Drug Discovery ; Information technology ; T58.5-58.64 ; Chemistry ; QD1-999
    Subject code 541
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher BMC
    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: Toxicokinetic analysis of the anticoagulant rodenticides warfarin & diphacinone in Egyptian fruit bats (Rousettus aegyptiacus) as a comparative sensitivity assessment for Bonin fruit bats (Pteropus pselaphon)

    Kazuki Takeda / Kosuke Manago / Ayuko Morita / Yusuke K. Kawai / Nobuaki Yasuo / Masakazu Sekijima / Yoshinori Ikenaka / Takuma Hashimoto / Ryuichi Minato / Yusuke Oyamada / Kazuo Horikoshi / Hajime Suzuki / Mayumi Ishizuka / Shouta M.M. Nakayama

    Ecotoxicology and Environmental Safety, Vol 243, Iss , Pp 113971- (2022)

    2022  

    Abstract: Anticoagulant rodenticides have been widely used to eliminate wild rodents, which as invasive species on remote islands can disturb ecosystems. Since rodenticides can cause wildlife poisoning, it is necessary to evaluate the sensitivity of local mammals ... ...

    Abstract Anticoagulant rodenticides have been widely used to eliminate wild rodents, which as invasive species on remote islands can disturb ecosystems. Since rodenticides can cause wildlife poisoning, it is necessary to evaluate the sensitivity of local mammals and birds to the poisons to ensure the rodenticides are used effectively. The Bonin Islands are an archipelago located 1000 km southeast of the Japanese mainland and are famous for the unique ecosystems. Here the first-generation anticoagulant rodenticide diphacinone has been used against introduced black rats (Rattus rattus). The only land mammal native to the archipelago is the Bonin fruit bat (Pteropus pselaphon), but little is known regarding its sensitivity to rodenticides. In this study, the Egyptian fruit bats (Rousettus aegyptiacus) was used as a model animal for in vivo pharmacokinetics and pharmacodynamics analysis and in vitro enzyme kinetics using their hepatic microsomal fractions. The structure of vitamin K epoxide reductase (VKORC1), the target protein of the rodenticide in the Bonin fruit bat, was predicted from its genome and its binding affinity to rodenticides was evaluated. The Egyptian fruit bats excreted diphacinone slowly and showed similar sensitivity to rats. In contrast, they excreted warfarin, another first-generation rodenticide, faster than rats and recovered from the toxic effect faster. An in silico binding study also indicated that the VKORC1 of fruit bats is relatively tolerant to warfarin, but binds strongly to diphacinone. These results suggest that even chemicals with the same mode of action display different sensitivities in different species: fruit bat species are relatively resistant to warfarin, but vulnerable to diphacinone.
    Keywords Chemical sensitivity ; Cytochrome P450 ; Molecular docking ; Pharmacokinetics ; Vitamin K epoxide reductase ; Environmental pollution ; TD172-193.5 ; Environmental sciences ; GE1-350
    Subject code 590
    Language English
    Publishing date 2022-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. 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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  7. 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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  8. 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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