Language：English  

DOI： 10.1021/acs.jmedchem.2c00749

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Language：English  

DOI： 10.1021/acs.joc.2c00508

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Autophagy inhibition is an attractive target for cancer therapy. In this study, we discovered inhibitors of Atg4B essential for autophagosome formation and evaluated their potential as therapeutics for prostate cancer. Seventeen compounds were identified as candidates after in silico screening and a thermal shift assay. Among them, compound 17 showed the most potent Atg4B inhibitory activity, inhibited autophagy induced by anti-castration-resistant prostate cancer (CRPC) drugs, and significantly enhanced apoptosis. Although 17 has been known as a phospholipase A2 (PLA2) inhibitor, other PLA2 inhibitors had no effect on Atg4B and autophagy. We then performed structural optimization based on molecular modeling and succeeded in developing 21f (by shortening the alkyl chain of 17), which was a potent competitive inhibitor for Atg4B (Ki = 3.1 μM) with declining PLA2 inhibitory potency. Compound 21f enhanced the anticancer activity of anti-CRPC drugs via autophagy inhibition. These findings suggest that 21f can be used as an adjuvant drug for therapy with anti-CRPC drugs.

DOI： 10.1021/acs.jmedchem.1c02113

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

The central role of Ebola virus (EBOV) VP40 in nascent virion assembly and budding from infected host cells makes it an important therapeutic target. The mechanism of dimerization, following oligomerization of VP40 leading to the production of virus-like particles (VLP) has never been investigated for the development of therapeutic candidates against Ebola disease. Molecular dynamics-based computational screening targeted VP40 dimer with 40,000,000 compounds selected 374 compounds. A novel in vitro screening assay selected two compounds, NUSU#1 and NUSU#2. Conventional VLP assays consistently showed that both compounds inhibited EBOV VP40-mediated VLP production. Intriguingly, NUSU#1 inhibited the VP40-mediated VLP production in other ebolavirus species and the Marburg virus, but did not inhibit Lassa virus Z-mediated VLP production. These results strongly suggested that the selected compounds are potential lead drug candidates against Filovirus disease via disruption of VP40-mediated particle production.

DOI： 10.1016/j.antiviral.2022.105267

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Influenza viruses are responsible for contagious respiratory illnesses in humans and cause seasonal epidemics and occasional pandemics worldwide. Previously, we identified a quinolinone derivative PA-49, which inhibited the influenza virus RNA-dependent RNA polymerase (RdRp) by targeting PA-PB1 interaction. This paper reports the structure optimization of PA-49, which resulted in the identification of 3-((dibenzylamino)methyl)quinolinone derivatives with more potent anti-influenza virus activity. During the optimization, the hit compound 89, which was more active than PA-49, was identified. Further optimization and scaffold hopping of 89 led to the most potent compounds 100 and a 1,8-naphthyridinone derivative 118, respectively. We conclusively determined that compounds 100 and 118 suppressed the replication of influenza virus and exhibited anti-influenza virus activity against both influenza virus types A and B in the range of 50% effective concentration (EC50) = 0.061-0.226 μM with low toxicity (50% cytotoxic concentration (CC50) >10 μM).

DOI： 10.1021/acs.jmedchem.1c01527

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.joc.1c02316

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.jpclett.1c02788

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.jctc.1c00475

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/v13071220

Publishing type：Part of collection (book)   Publisher：Springer Singapore  

DOI： 10.1007/978-981-15-9235-5_4

Language：Japanese   Publisher：Wiley  

DOI： 10.1002/chem.202004769

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.cplett.2020.138103

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>
Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-<sc>d</sc>-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) <italic>Candida</italic> and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR <italic>Candida auris</italic> in only 5 min, as well as <italic>Candida</italic>-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.

DOI： 10.1038/s41598-020-74749-8

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Other Link： http://www.nature.com/articles/s41598-020-74749-8

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s13311-020-00903-9

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Other Link： http://link.springer.com/article/10.1007/s13311-020-00903-9/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The emergence of resistance to currently available anti-influenza drugs has heightened the need for antivirals with novel mechanisms of action. The influenza A virus (IAV) nucleoprotein (NP) is highly conserved and essential for the formation of viral ribonucleoprotein (vRNP), which serves as the template for replication and transcription. Recently, using in silico screening, we identified an antiviral compound designated NUD-1 (a 4-hydroxyquinolinone derivative) as a potential inhibitor of NP. In this study, we further analyzed the interaction between NUD-1 and NP and found that the compound interferes with the oligomerization of NP, which is required for vRNP formation, leading to the suppression of viral transcription, protein synthesis, and nuclear export of NP. We further assessed the selection of resistant variants by serially passaging a clinical isolate of the 2009 H1N1 pandemic influenza virus in the presence of NUD-1 or oseltamivir. NUD-1 did not select for resistant variants after nine passages, whereas oseltamivir selected for resistant variants after five passages. Our data demonstrate that NUD-1 interferes with the oligomerization of NP and less likely induces drug-resistant variants than oseltamivir; hence, it is a potential lead compound for the development of novel anti-influenza drugs.

DOI： 10.3390/v12030337

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Society of Computer Chemistry, Japan  

<p>An RNA aptamer that binds with high affinity and specificity to human immunoglobulin G (IgG) is a 24-mer single-stranded oligonucleotide containing 2′-fluoro pyrimidine nucleotides. Using X-ray crystallographic analysis, a Ca²⁺ ion was reported as being located near the G7 phosphate of the RNA aptamer. Surface plasmon resonance analysis showed that the RNA aptamer could not bind to IgG in a buffer without Ca²⁺ ions. To elucidate the role of Ca²⁺ ions in the binding of the RNA aptamer to IgG, we performed molecular dynamics simulation for the RNA aptamer/IgG complex with and without Ca²⁺ ions in a solvent. In the presence of Ca²⁺ ions, the RMSD of the RNA aptamer backbone remained below approximately 3.0 Å from the crystal structure during a 1,500-ns simulation. The distance between the centroids of the RNA aptamer and IgG was maintained between the centroids in the crystal structure. However, in the absence of Ca²⁺ ions, the RMSD increased and the structure of the RNA aptamer changed from the initial structure. These results indicate that Ca²⁺ ions play a role in maintaining the conformation of the RNA aptamer to the binding form.</p>

DOI： 10.2477/jccj.2019-0051

Language：Japanese  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Society of Computer Chemistry, Japan  

<p>The reaction process and steric situations of novel basic and chiral catalyst Diels-Alder reactions by Kagan et al. were speculated by IRC of PM7 simulation for the three molecules reactions clearly. The addition reactions of enolic dienes (<b>1</b>) with dienophiles (<b>2</b>) by amines (<b>3</b>) such as (<i>S</i>)-(+)-prolinol / (<i>R</i>)-(−)-prolinol proceeded via lower energy reaction complexes (RC) and transition states (TS) of two steps. The steric shapes by IRC (Figure 2 ∼ 6) showed the clear interactions between the reaction points, and of OH with amine moieties in the <b>1·3, 1·3·2</b> and TS complexes, to give high stereoselective adducts. IRC of some reactions also guesses right the Michael reaction selectivity. The handy PM7 simulation is recommended for usual chemical growth.</p>

DOI： 10.2477/jccj.2021-0011

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.cplett.2019.136854

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed. METHODOLOGY/PRINCIPAL FINDINGS: Here, to develop new drugs against amoebiasis, we focused on E. histolytica adenosine 5'-phosphosulfate kinase (EhAPSK), an essential enzyme in Entamoeba sulfolipid metabolism. Fatty alcohol disulfates and cholesteryl sulfate, sulfolipids synthesized in Entamoeba, play important roles in trophozoite proliferation and cyst formation. These processes are closely associated with clinical manifestation and severe pathogenesis of amoebiasis and with disease transmission, respectively. We validated a combination approach of in silico molecular docking analysis and an in vitro enzyme activity assay for large scale screening. Docking simulation ranked the binding free energy between a homology modeling structure of EhAPSK and 400 compounds. The 400 compounds were also screened by a 96-well plate-based in vitro APSK activity assay. Among fifteen compounds identified as EhAPSK inhibitors by the in vitro system, six were ranked by the in silico analysis as having high affinity toward EhAPSK. Furthermore, 2-(3-fluorophenoxy)-N-[4-(2-pyridyl)thiazol-2-yl]-acetamide, 3-phenyl-N-[4-(2-pyridyl)thiazol-2-yl]-imidazole-4-carboxamide, and auranofin, which were identified as EhAPSK inhibitors by both in silico and in vitro analyses, halted not only Entamoeba trophozoite proliferation but also cyst formation. These three compounds also dose-dependently impaired the synthesis of sulfolipids in E. histolytica. CONCLUSIONS/SIGNIFICANCE: Hence, the combined approach of in silico and in vitro-based EhAPSK analyses identified compounds that can be evaluated for their effects on Entamoeba. This can provide leads for the development of new anti-amoebic and amoebiasis transmission-blocking drugs. This strategy can also be applied to identify specific APSK inhibitors, which will benefit research into sulfur metabolism and the ubiquitous pathway terminally synthesizing essential sulfur-containing biomolecules.

DOI： 10.1371/journal.pntd.0007633

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1099/jgv.0.001286

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Language：English   Publishing type：Research paper (scientific journal)  

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that lack therapeutic solutions. Here, we show that the molecular chaperone (N,N'-([cyclohexylmethylene]di-4,1-phenylene)bis(2-[1-pyrrolidinyl]acetamide)), designed via docking simulations, molecular dynamics simulations and quantum chemical calculations, slows down the progress of TSEs. In vitro, the designer molecular chaperone stabilizes the normal cellular prion protein, eradicates prions in infected cells, prevents the formation of drug-resistant strains and directly inhibits the interaction between prions and abnormal aggregates, as shown via real-time quaking-induced conversion and in vitro conversion NMR. Weekly intraperitoneal injection of the chaperone in prion-infected mice prolonged their survival, and weekly intravenous administration of the compound in macaques infected with bovine TSE slowed down the development of neurological and psychological symptoms and reduced the concentration of disease-associated biomarkers in the animals' cerebrospinal fluid. The de novo rational design of chaperone compounds could lead to therapeutics that can bind to different prion protein strains to ameliorate the pathology of TSEs.

DOI： 10.1038/s41551-019-0349-8

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Alectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet. METHODS: We established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico, we developed a modified computational molecular dynamic simulation (MP-CAFEE). FINDINGS: We identified 14 lorlatinib-resistant ALK-compound mutants, including several mutants that were recently discovered in lorlatinib-resistant patients. Some of these compound mutants were found to be sensitive to early generation ALK-TKIs and several BCR-ABL inhibitors. Using our original computational simulation, we succeeded in demonstrating a clear linear correlation between binding free energy and in vitro experimental IC50 value of several ALK-TKIs to single- or compound-mutated EML4-ALK expressing Ba/F3 cells and in recapitulating the tendency of the binding affinity reduction by double mutations found in this study. Computational simulation revealed that ALK-L1256F single mutant conferred resistance to lorlatinib but increased the sensitivity to alectinib. INTERPRETATION: We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. FUND: This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants.

DOI： 10.1016/j.ebiom.2019.01.019

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

In modern praxis, a knowledge-driven design of pharmaceutical compounds relies heavily on protein structure data. Nonetheless, quantification of the interaction between protein and ligand is of great importance in the theoretical evaluation of the ability of a pharmaceutical compound to comply with certain expectations. The FMO (fragment molecular orbital) method is handy in this regard. However, the physical complexity and the number of the interactions within a protein-ligand complex renders analysis of the results somewhat complicated. This situation prompted us to develop the 3D-visualization of interaction energies in protein (3D-VIEP) method; the toolkit AnalysisFMO, which should enable a more efficient and convenient workflow with FMO data generated by quantum-chemical packages such as GAMESS, PAICS, and ABINIT-MP. AnalysisFMO consists of two separate units, RbAnalysisFMO, and the PyMOL plugins. The former can extract interfragment interaction energies (IFIEs) or pair interaction energies (PIEs) from the FMO output files generated by the aforementioned quantum-chemical packages. The PyMOL plugins enable visualization of IFIEs or PIEs in the protein structure in PyMOL. We demonstrate the use of this tool on a lectin protein from Burkholderia cenocepacia in which FMO analysis revealed the existence of a new interaction between G1y84 and fucose. Moreover, we found that second-shell interactions are crucial in forming the sugar binding site. In the case of bilirubin oxidase from Myrothecium verrucaria (MvBO), we predict that interactions between Asp105 and three His residues (His401, His403, and His136) are essential for optimally positioning the His residues to coordinate Cu atoms to form one Type 2 and two Type 3 Cu ions.

DOI： 10.1021/acs.jcim.8b00649

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jcc.25368

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.jpcb.8b04509

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Prion diseases are transmissible neurodegenerative disorders of humans and animals, which are characterized by the aggregation of abnormal prion protein (PrPSc) in the central nervous system. Although several small compounds that bind to normal PrP (PrPC) have been shown to inhibit structural conversion of the protein, an effective therapy for human prion disease remains to be established. In this study, we screened 1200 existing drugs approved by the US Food and Drug Administration (FDA) for anti-prion activity using surface plasmon resonance imaging (SPRi). Of these drugs, 31 showed strong binding activity to recombinant human PrP, and three of these reduced the accumulation of PrPSc in prion-infected cells. One of the active compounds, alprenolol hydrochloride, which is used clinically as a β-adrenergic blocker for hypertension, also reduced the accumulation of PrPSc in the brains of prion-infected mice at the middle stage of the disease when the drug was administered orally with their daily water from the day after infection. Docking simulation analysis suggested that alprenolol hydrochloride fitted into the hotspot within mouse PrPC, which is known as the most fragile structure within the protein. These findings provide evidence that SPRi is useful in identifying effective drug candidates for neurodegenerative diseases caused by abnormal protein aggregation, such as prion diseases.

DOI： 10.1007/s12035-018-1088-7

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Inc.  

Efficient quantum chemical calculations of electrostatic properties, namely, the electron density (EDN), electrostatic potential (ESP), and electric field (EFL), were performed using the fragment molecular orbital (FMO) method. The numerical errors associated with the FMO scheme were examined at the HF, MP2, and RI-MP2 levels of theory using 4 small peptides. As a result, the FMO errors in the EDN, ESP, and EFL were significantly smaller than the magnitude of the electron correlation effects, which indicated that the FMO method provides sufficiently accurate values of electrostatic properties. In addition, an attempt to reduce the computational effort was proposed by combining the FMO scheme and a point charge approximation. The error due to this approximation was examined using 2 proteins, prion protein and human immunodeficiency virus type 1 protease. As illustrative examples, the ESP values at the molecular surface of these proteins were calculated at the MP2 level of theory.

DOI： 10.1002/qua.25535

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Language：English   Publishing type：Research paper (scientific journal)  

Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted brain-derived neurotrophic factor in vitro and of monocyte chemotactic protein-1 at day 7 in vivo were both significantly higher for young hMSC compared with old hMSC. Male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion that received young hMSC (trans-arterially at 24 h after stroke) showed better behavioural recovery with prevention of brain atrophy compared with rats that received old hMSC. Histological analysis of the peri-infarct cortex showed that rats treated with young hMSC had significantly fewer microglia and more vessels covered with pericytes. Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment, which was more pronounced for young hMSC. Aging of hMSC may be a critical factor that affects cell therapy outcomes, and transplantation of young hMSC appears to provide better functional recovery through anti-inflammatory effects, vessel maturation, and neurogenesis potentially by the dominance of trophic factor secretion.

DOI： 10.1177/0271678X17731964

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Influenza virus infections are serious public health concerns throughout the world. The development of compounds with novel mechanisms of action is urgently required due to the emergence of viruses with resistance to the currently-approved anti-influenza viral drugs. We performed in silico screening using a structure-based drug discovery algorithm called Nagasaki University Docking Engine ( NUDE), which is optimised for a GPU-based supercomputer (DEstination for Gpu Intensive MAchine; DEGIMA), by targeting influenza viral PA protein. The compounds selected by NUDE were tested for anti-influenza virus activity using a cell-based assay. The most potent compound, designated as PA-49, is a mediumsized quinolinone derivative bearing a tetrazole moiety, and it inhibited the replication of influenza virus A/WSN/33 at a half maximal inhibitory concentration of 0.47 mu M. PA-49 has the ability to bind PA and its anti-influenza activity was promising against various influenza strains, including a clinical isolate of A(H1N1) pdm09 and type B viruses. The docking simulation suggested that PA-49 interrupts the PAPB1 interface where important amino acids are mostly conserved in the virus strains tested, suggesting the strain independent utility. Because our NUDE/DEGIMA system is rapid and efficient, it may help effective drug discovery against the influenza virus and other emerging viruses.

DOI： 10.1038/s41598-017-10021-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC STUDY XENOBIOTICS  

The efficacy of the antiepileptic drug VPA is decreased by co-administered carbapenems (CBPMs). The mechanism of CBPM selective inhibition of acylpeptide hydrolase (APEH) hydrolysis of VPA-glucuronide (VPA-G) to VPA is unclear due to the lack of APEH structural information. Here we performed homology modeling of the three-dimensional structure of APEH and subsequent docking simulations with a modeled structure to understand this mechanism. Docking simulations indicated that four groups of binding structures were involved in the binding of VPA-G, panipenem, and meropenem to APEH, but only one or two binding structures were involved in the binding of meropenem with an open beta-lactam ring structure and other antibiotics involving ampicillin. One of the four VPA-G binding structures was close enough to the APEH catalytic triad to facilitate VPA-G hydrolysis. This binding structure was also the most stable binding structure for panipenem, suggesting potential inhibition of VPA-G hydrolysis by panipenem. Fragment molecular orbital calculations of interaction energies of amino acid residues of APEH with VPA-G, panipenem, and meropenem indicated that the binding structure for panipenem closest to the catalytic triad is stabilized upon APEH interaction. These data suggest that APEH binding characteristics with CBPMs may help explain the selective inhibition of APEH by CBPMs. (C) 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dmpk.2017.04.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Influenza viruses have acquired resistance to approved neuraminidase-targeting drugs, increasing the need for new drug targets for the development of novel anti-influenza drugs. Nucleoprotein (NP) is an attractive target since it has an indispensable role in virus replication and its amino acid sequence is well conserved. In this study, we aimed to identify new inhibitors of the NP using a structure-based drug discovery algorithm, named Nagasaki University Docking Engine (NUDE), which has been established especially for the Destination for GPU Intensive Machine (DEGIMA) supercomputer. The hit compounds that showed high binding scores during in silico screening were subsequently evaluated for anti-influenza virus effects using a cell-based assay. A 4-hydroxyquinolinone compound, designated as NUD-1, was found to inhibit the replication of influenza virus in cultured cells. Analysis of binding between NUD-1 and NP using surface plasmon resonance assay and fragment molecular orbital calculations confirmed that NUD-1 binds to NP and could interfere with NP-NP interactions essential for virus replication. Time-of-addition experiments showed that the compound inhibited the mid-stage of infection, corresponding to assembly of the NP and other viral proteins. Moreover, NUD-1 was also effective against various types of influenza A viruses including a clinical isolate of A(H1N1)pdm09 influenza with a 50% inhibitory concentration range of 1.8-2.1 mu M. Our data demonstrate that the combined use of NUDE system followed by the cell-based assay is useful to obtain lead compounds for the development of novel anti-influenza drugs.

DOI： 10.1371/journal.pone.0173582

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DOI： 10.1021/acs.jpcb.6b09328

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DOI： 10.1007/s10822-016-9967-3

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DOI： 10.1016/j.ebiom.2016.06.010

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DOI： 10.1021/acs.jmedchem.5b01863

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DOI： 10.1038/srep23454

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DOI： 10.1038/ncomms10356

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DOI： 10.1248/yakushi.15-00230-5

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DOI： 10.2751/jcac.16.15

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DOI： 10.1016/j.chemphys.2015.08.007

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DOI： 10.1007/s10265-015-0740-9

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DOI： 10.2477/jccj.2014-0056

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DOI： 10.11546/cicsj.31.71

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DOI： 10.1039/C3CP42761G

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DOI： 10.1016/j.cplett.2012.12.063

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DOI： 10.1021/jz201697x

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DOI： 10.1016/j.cplett.2010.09.071

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DOI： 10.1273/cbij.10.24

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DOI： 10.1524/zkri.2008.0033

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DOI： 10.1002/jcc.21265

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DOI： 10.1016/j.cplett.2009.04.045

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DOI： 10.1021/jp808151c

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DOI： 10.1016/j.cplett.2008.11.044

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DOI： 10.1021/jp803369x

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DOI： 10.1016/j.cplett.2008.08.022

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DOI： 10.1002/jcc.21025

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DOI： 10.1021/ja710038c

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DOI： 10.1016/j.cplett.2007.11.084

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DOI： 10.1007/s00214-007-0374-7

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DOI： 10.1016/j.cplett.2007.02.016

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DOI： 10.1007/s00214-006-0181-6

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DOI： 10.1016/j.cplett.2006.11.088

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DOI： 10.1007/s00214-006-0171-8

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DOI： 10.1016/j.cplett.2006.09.015

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DOI： 10.1016/j.cplett.2005.11.014

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DOI： 10.1063/1.1989318

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DOI： 1016/j.cplett.2005.06.117

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DOI： 10.1063/1.1851975

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DOI： 10.1016/j.cplett.2004.07.055

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DOI： 10.1063/1.1406975

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DOI： 10.1103/PhysRevLett.86.3654

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Language：English   Publisher：生命科学系学会合同年次大会運営事務局  

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J-GLOBAL

Event date： 2023.3

Language：Japanese   Presentation type：Poster presentation  

Event date： 2023.3

Language：Japanese   Presentation type：Poster presentation  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2023.3

Language：Japanese   Presentation type：Poster presentation  

Event date： 2023.1

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2022.11

Language：Japanese   Presentation type：Poster presentation  

Event date： 2022.10

Language：English   Presentation type：Poster presentation  

Event date： 2022.10

Language：Japanese   Presentation type：Poster presentation  

Venue：横浜   Country：Japan  

Event date： 2022.10

Language：English   Presentation type：Oral presentation (invited, special)  

Country：United States  

Event date： 2022.10

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2022.10

Language：English   Presentation type：Oral presentation (invited, special)  

Event date： 2022.9

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2022.9

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2022.9

Language：English   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2022.9

Language：English   Presentation type：Oral presentation (invited, special)  

Event date： 2022.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2022.8

Language：English   Presentation type：Oral presentation (general)  

Event date： 2021.11

Language：English   Presentation type：Poster presentation  

Event date： 2021.11

Language：English   Presentation type：Poster presentation  

Event date： 2021.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：遠隔   Country：Japan  

Event date： 2021.10

Language：Japanese   Presentation type：Poster presentation  

Event date： 2021.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2021.10

Language：Japanese   Presentation type：Poster presentation  

Event date： 2021.10

Language：Japanese   Presentation type：Poster presentation  

Event date： 2021.10

Language：Japanese   Presentation type：Poster presentation  

Event date： 2021.7

Language：Japanese   Presentation type：Poster presentation  

Event date： 2021.3

Language：Japanese  

Event date： 2021.3

Language：Japanese   Presentation type：Poster presentation  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：遠隔   Country：Japan  

Event date： 2020.11

Language：Japanese   Presentation type：Poster presentation  

Event date： 2020.11

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：鹿児島   Country：Japan  

Event date： 2020.11

Language：Japanese   Presentation type：Poster presentation  

Event date： 2020.9 - 2020.11

Language：Japanese   Presentation type：Poster presentation  

Venue：遠隔   Country：Japan  

Event date： 2019.12

Language：Japanese   Presentation type：Poster presentation  

Event date： 2019.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2019.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2019.10

Language：Japanese   Presentation type：Poster presentation  

Venue：広島  

Event date： 2019.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2019.10

Language：English   Presentation type：Oral presentation (general)  

Venue： Fargo, USA  

Event date： 2019.9

Language：Japanese   Presentation type：Poster presentation  

Venue：静岡  

Event date： 2019.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：熊本  

Event date： 2019.6

Language：Japanese   Presentation type：Poster presentation  

Venue：神戸  

Event date： 2019.6

Language：Japanese   Presentation type：Poster presentation  

Venue：神戸  

Event date： 2019.6

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2019.3

Language：Japanese   Presentation type：Poster presentation  

Venue：神戸  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Event date： 2018.11

Language：Japanese   Presentation type：Poster presentation  

Venue：横浜  

Event date： 2018.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2018.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2018.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2018.10

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2018.9

Language：English   Presentation type：Poster presentation  

Venue：北九州  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：北九州  

Event date： 2018.8

Language：Japanese   Presentation type：Poster presentation  

Venue：福岡  

Event date： 2018.3

Language：Japanese   Presentation type：Poster presentation  

Venue：金沢  

Event date： 2017.12

Language：Japanese   Presentation type：Poster presentation  

Venue：神戸  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：船堀  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2017.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2017.9

Language：Japanese   Presentation type：Poster presentation  

Venue：盛岡  

Event date： 2017.9

Language：English   Presentation type：Poster presentation  

Venue：Marburg, Germany  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：大阪  

Event date： 2017.8

Language：English   Presentation type：Poster presentation  

Venue：Vienna, Austria  

Event date： 2017.7

Language：English   Presentation type：Poster presentation  

Venue：Singapore  

Event date： 2017.6

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2017.5

Language：English   Presentation type：Poster presentation  

Venue：Nagasaki, Japan  

Event date： 2017.3

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2017.3

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2017.3

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2016.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：郡山  

Event date： 2016.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2016.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2016.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2016.10

Language：English   Presentation type：Poster presentation  

Venue：東京  

Event date： 2016.9

Language：English   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2016.9

Language：Japanese   Presentation type：Poster presentation  

Venue：郡山  

Event date： 2016.9

Language：English   Presentation type：Poster presentation  

Venue：Awaji, Japan  

Event date： 2016.9

Language：English   Presentation type：Oral presentation (general)  

Venue：淡路島  

Event date： 2016.7

Language：English   Presentation type：Poster presentation  

Venue：Tokyo, Japan  

Event date： 2016.7 - 2017.7

Language：English   Presentation type：Oral presentation (general)  

Venue：kannonji, Japan  

Event date： 2016.6

Language：Japanese   Presentation type：Poster presentation  

Venue：福岡  

Event date： 2016.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2016.3

Language：Japanese   Presentation type：Poster presentation  

Venue：横浜  

Event date： 2016.3

Language：Japanese   Presentation type：Poster presentation  

Venue：京都  

Event date： 2015.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：郡山  

Event date： 2015.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：沖縄  

Event date： 2015.10

Language：Japanese   Presentation type：Poster presentation  

Venue：富山  

Event date： 2015.9

Language：English   Presentation type：Poster presentation  

Venue：Awaji, Japan  

Event date： 2015.3

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：神戸  

Event date： 2014.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：船堀  

Event date： 2014.10

Language：Japanese   Presentation type：Poster presentation  

Venue：郡山  

Event date： 2014.10

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2014.3

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：熊本  

Event date： 2013.10

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2013.6

Language：English   Presentation type：Oral presentation (general)  

Venue：Boston  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神奈川  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神奈川  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神奈川  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神奈川  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2012.10

Language：English   Presentation type：Poster presentation  

Venue：Honolulu, Hawaii  

Event date： 2012.10

Language：English   Presentation type：Poster presentation  

Venue：Honolulu, Hawaii  

Event date： 2012.10

Language：English   Presentation type：Poster presentation  

Venue：Honolulu, Hawaii  

Event date： 2012.10

Language：English   Presentation type：Poster presentation  

Venue：Honolulu, Hawaii  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：室蘭  

Event date： 2012.9

Language：Japanese   Presentation type：Poster presentation  

Venue：横浜  

Event date： 2012.9

Language：Japanese   Presentation type：Poster presentation  

Venue：小倉  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松山  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松山  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松山  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松山  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：室蘭  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：室蘭  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：室蘭  

Event date： 2012.6

Language：English   Presentation type：Oral presentation (invited, special)  

Event date： 2012.6

Language：Japanese   Presentation type：Poster presentation  

Venue：名古屋  

Event date： 2012.5

Language：English   Presentation type：Oral presentation (invited, special)  

Venue：名古屋  

Event date： 2012.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸  

Event date： 2012.3

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌  

Event date： 2011.12

Language：English   Presentation type：Poster presentation  

Venue：Yokohama, Japan  

Event date： 2011.11

Language：English   Presentation type：Poster presentation  

Venue：Tokyo, Japan  

Event date： 2011.9

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌  

Event date： 2011.7

Language：English   Presentation type：Poster presentation  

Venue：Santiago, Spain  

Event date： 2010.9

Language：English   Presentation type：Oral presentation (invited, special)  

Event date： 2010.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪  

Event date： 2010.3

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：岡山  

Event date： 2010.1

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2009.7

Language：English   Presentation type：Oral presentation (invited, special)  

Venue：東京  

Event date： 2009.3

Language：Japanese   Presentation type：Poster presentation  

Venue：習志野  

Event date： 2009.1

Language：Japanese   Presentation type：Poster presentation  

Venue：岡崎  

Event date： 2009.1

Language：Japanese   Presentation type：Poster presentation  

Venue：岡崎  

Event date： 2008.12

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：福岡  

Event date： 2008.12

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2008.10

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2008.9

Language：English   Presentation type：Poster presentation  

Venue：Sydney, Australia  

Event date： 2008.9

Language：Japanese   Presentation type：Poster presentation  

Venue：福岡  

Event date： 2008.9

Language：Japanese   Presentation type：Poster presentation  

Venue：福岡  

Event date： 2008.8

Language：English   Presentation type：Poster presentation  

Venue：北海道  

Event date： 2008.3

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2008.3

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2007.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2007.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2007.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2007.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2007.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

Event date： 2006.10

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2006.9

Language：Japanese   Presentation type：Poster presentation  

Venue：静岡  

Event date： 2006.9

Language：Japanese   Presentation type：Poster presentation  

Venue：静岡  

Event date： 2006.5

Language：English   Presentation type：Poster presentation  

Venue：Kyoto, Japan  

Event date： 2006.5

Language：English   Presentation type：Poster presentation  

Venue：Kyoto, Japan  

Event date： 2006.3

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台  

Event date： 2005.9

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2005.9

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2005.9

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 2004.9

Language：Japanese   Presentation type：Poster presentation  

Venue：広島  

Event date： 2004.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島  

Event date： 2004.5

Language：English   Presentation type：Poster presentation  

Venue：札幌  

Event date： 2003.9

Language：Japanese   Presentation type：Oral presentation (keynote)  

Venue：京都  

Event date： 2002.11

Language：Japanese   Presentation type：Poster presentation  

Venue：岡崎  

Event date： 2002.10

Language：Japanese   Presentation type：Poster presentation  

Venue：神戸  

Event date： 2001.9

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌  

Event date： 2001.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌  

Event date： 2000.9

Language：Japanese   Presentation type：Poster presentation  

Venue：東京  

Event date： 1999.9

Language：Japanese   Presentation type：Poster presentation  

Venue：大阪  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Application no：特願2017-23175  Date applied：2017.2

Announcement no：特開2018-126117  Date announced：2018.8

Country of applicant：Domestic  

Application no：特願2016-170349  Date applied：2016.8

Announcement no：特開2018-35099  Date announced：2018.3

Country of applicant：Domestic