Publications by authors named "Noriyuki Kurita"

51 Publications

Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations.

Biophys Chem 2021 Aug 29;275:106608. Epub 2021 Apr 29.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan. Electronic address:

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro. We furthermore proposed novel compounds based on niaziminin and investigated their binding properties to Mpro. The results reveal that the introduction of a hydroxyl group into niaziminin enhances its binding affinity to Mpro. These niaziminin derivatives can be promising candidate drugs for the treatment of COVID-19.
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http://dx.doi.org/10.1016/j.bpc.2021.106608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084281PMC
August 2021

Proposal of novel potent inhibitors against androgen receptor based on ab initio molecular orbital calculations.

J Mol Graph Model 2021 06 18;105:107873. Epub 2021 Feb 18.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan. Electronic address:

The androgen receptor (AR), a family of nuclear receptor proteins, stimulates the transcription of androgen-responsive genes. As its abnormal activation can cause the progression of prostate cancer, numerous types of ligands for AR have been developed as promising antagonists for the treatment of prostate cancer. We previously investigated the specific interactions between AR and nine types of existing non-steroidal ligands, using molecular simulations based on molecular mechanics and ab initio fragment molecular orbital methods. The results were confirmed to be comparable to the binding affinities of these ligands observed in experiments. We here propose novel ligands as potent inhibitors against AR and investigate their binding properties to AR, using the same molecular simulations. The results indicate that the most promising ligand binds stronger to AR than the existing non-steroidal ligands, and that our proposed ligand binds strongly to a mutant-type AR, which has drug resistance to the existing non-steroidal ligands.
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http://dx.doi.org/10.1016/j.jmgm.2021.107873DOI Listing
June 2021

FMODB: The World's First Database of Quantum Mechanical Calculations for Biomacromolecules Based on the Fragment Molecular Orbital Method.

J Chem Inf Model 2021 02 29;61(2):777-794. Epub 2021 Jan 29.

RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

We developed the world's first web-based public database for the storage, management, and sharing of fragment molecular orbital (FMO) calculation data sets describing the complex interactions between biomacromolecules, named FMO Database (https://drugdesign.riken.jp/FMODB/). Each entry in the database contains relevant background information on how the data was compiled as well as the total energy of each molecular system and interfragment interaction energy (IFIE) and pair interaction energy decomposition analysis (PIEDA) values. Currently, the database contains more than 13 600 FMO calculation data sets, and a comprehensive search function implemented at the front-end. The procedure for selecting target proteins, preprocessing the experimental structures, construction of the database, and details of the database front-end were described. Then, we demonstrated a use of the FMODB by comparing IFIE value distributions of hydrogen bond, ion-pair, and XH/π interactions obtained by FMO method to those by molecular mechanics approach. From the comparison, the statistical analysis of the data provided standard reference values for the three types of interactions that will be useful for determining whether each interaction in a given system is relatively strong or weak compared to the interactions contained within the data in the FMODB. In the final part, we demonstrate the use of the database to examine the contribution of halogen atoms to the binding affinity between human cathepsin L and its inhibitors. We found that the electrostatic term derived by PIEDA greatly correlated with the binding affinities of the halogen containing cathepsin L inhibitors, indicating the importance of QM calculation for quantitative analysis of halogen interactions. Thus, the FMO calculation data in FMODB will be useful for conducting statistical analyses to drug discovery, for conducting molecular recognition studies in structural biology, and for other studies involving quantum mechanics-based interactions.
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http://dx.doi.org/10.1021/acs.jcim.0c01062DOI Listing
February 2021

Proposal of novel inhibitors for vitamin-D receptor: Molecular docking, molecular mechanics and ab initio molecular orbital simulations.

Biophys Chem 2021 03 1;270:106540. Epub 2021 Jan 1.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan. Electronic address:

The specific binding of active vitamin-D to the vitamin-D receptor (VDR) is closely related to the onset of immunological diseases. To inhibit the binding, various compounds have been developed as potent inhibitors against VDR. Among them, a compound NS-54c, which was developed based on the first VDR antagonist TEI-9647 (25-dehydro-1α-hydroxyvitamin D-26,23-lactone), was revealed to posse almost 1000-fold improved antagonistic activity over the original TEI-9647. However, the reason for this significant improvement has not been elucidated. In the present study, we investigated the specific interactions between VDR and these inhibitors, using molecular simulations based on molecular docking, molecular mechanics and ab initio fragment molecular orbital calculations. Based on the results simulated, we furthermore proposed novel inhibitors and investigated their binding properties to VDR. The results elucidate that the replacement of propyl group at the 24th site of NS-54c by a phenethyl group can enhance the binding affinity of the inhibitor to VDR. This finding provides useful information for developing novel potent inhibitors against VDR.
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http://dx.doi.org/10.1016/j.bpc.2020.106540DOI Listing
March 2021

Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations.

Antibiotics (Basel) 2020 Nov 26;9(12). Epub 2020 Nov 26.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan.

The inhibition of a bacterial cell division protein, filamentous temperature-sensitive Z (FtsZ), prevents the reproduction of . To propose potent inhibitors of FtsZ, the binding properties of FtsZ with various derivatives of Zantrin ZZ3 were investigated at an electronic level, using molecular simulations. We here employed protein-ligand docking, classical molecular mechanics (MM) optimizations, and ab initio fragment molecular orbital (FMO) calculations. Based on the specific interactions between FtsZ and the derivatives, as determined by FMO calculations, we proposed novel ligands, which can strongly bind to FtsZ and inhibit its aggregations. The introduction of a hydroxyl group into ZZ3 was found to enhance its binding affinity to FtsZ.
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http://dx.doi.org/10.3390/antibiotics9120846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761175PMC
November 2020

Structural change of retinoic-acid receptor-related orphan receptor induced by binding of inverse-agonist: Molecular dynamics and molecular orbital simulations.

Comput Struct Biotechnol J 2020 25;18:1676-1685. Epub 2020 Jun 25.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan.

To elucidate structural changes in the retinoic acid receptor-related orphan receptor gamma (RORγt) induced by the binding of an agonist or an inverse agonist, we conducted molecular dynamics (MD) simulations in explicit water. In addition, fragment molecular orbital calculations were carried out for certain characteristic structures obtained from the MD simulations to reveal important interactions between the amino acid residues of RORγt, and to distinguish the different effects in the binding of an agonist and an inverse agonist on the structure of RORγt. The results elucidate that the hydrogen bond between His479 of helix11 (H11) and Tyr502 of helix12 (H12) is important to keep the H12 conformation in the agonist-bound RORγt. In contrast, in the inverse-agonist-bound RORγt, the side chain of His479 rotates, significantly weakening the interaction between His479 and Tyr502, leading to a conformational change in H12. Therefore, the present molecular simulations clearly indicate that the conformational change in the side chain of His479 in the inverse-agonist-bound RORγt is the main reason for the H12 destabilization induced by the binding of the inverse agonist. Such a conformational change does not occur on the binding of the agonist in RORγt, owing to the strong hydrogen bond between His479 and Tyr502.
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http://dx.doi.org/10.1016/j.csbj.2020.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338990PMC
June 2020

Specific interactions between tau protein and curcumin derivatives: Molecular docking and ab initio molecular orbital simulations.

J Mol Graph Model 2020 07 31;98:107611. Epub 2020 Mar 31.

Department of Computer Science and Engineering, Toyohashi University of Technology, Toyohashi, 441-8580, Japan. Electronic address:

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world, and there is currently no potent medicine for the treatment of ADs. Curcumin, a primary chemical contained in the ancient Indian herb known as turmeric, has been extensively studied and shown to be effective in inhibiting the aggregations of amyloid-β and tau proteins, both of which are observed in the brains of AD patients. In the present study, we focused on the tau protein and investigated its specific interactions with curcumin derivatives, using molecular simulations based on molecular docking, molecular mechanics and ab initio fragment molecular orbital calculations. Based on the results, we attempted to propose novel potent inhibitors against the tau protein aggregation. Our molecular simulations provide useful information for developing novel medicines for the treatment of ADs.
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http://dx.doi.org/10.1016/j.jmgm.2020.107611DOI Listing
July 2020

Protonation states of central amino acids in a zinc metalloprotease complexed with inhibitor: Molecular mechanics optimizations and ab initio molecular orbital calculations.

Biophys Chem 2020 06 1;261:106368. Epub 2020 Apr 1.

Department of Computer Science and Engineering, Toyohashi University of Technology, Toyohashi 441-8580, Japan. Electronic address:

The zinc-metalloprotease pseudolysin (PLN) secreted from bacteria degrades extracellular proteins to produce bacterial nutrition. Since PLN has a Zn ion at the inhibitor-binding site, the interactions between Zn and PLN residues as well as inhibitor can be significantly changed depending on the protonation states of PLN residues at the inhibitor-binding site. To determine stable protonation states of these residues, we here considered different protonation states for Glu and His residues located around Zn and investigated the electronic states of the PLN + inhibitor complex, using ab initio molecular simulations. The protonation state of His223 was found to significantly affect the specific interactions between PLN and the inhibitor.
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http://dx.doi.org/10.1016/j.bpc.2020.106368DOI Listing
June 2020

Design of galardine analogs as putative psudolysin inhibitors based on fragment molecular orbital calculations.

J Biomol Struct Dyn 2020 Jul 29;38(11):3307-3317. Epub 2019 Aug 29.

Department of Computer Science and Engineering, Toyohashi University of Technology, Toyohashi, Japan.

Pseudolysin (PLN) is a metalloproteinase secreted from bacteria that degrades extracellular proteins to produce bacterial nutrition. It is thus expected that inhibitors against PLN can suppress the growth of bacteria and their pandemic spread. In addition, since these inhibitors do not attack to bacteria directly, there is a reduced risk for producing drug-resistant bacteria. On the other hand, as PLN has large structural similarity in the active sites with human matrix-metalloproteinases (MMPs), there is a possibility that the inhibitors for PLN also inhibit MMP activity, resulting in a loss of necessary nutrients to be produced by MMPs. Therefore, it is required the agents inhibiting the activity of only PLN not MMPs. In the present study, we employed a hydroxamate compound galardin, which has a significant inhibition effect against PLN and MMP, and investigated its specific interactions with PLN/MMP at atomic and electronic levels, by use of molecular simulations. Based on the results, we proposed several derivatives of galardin and elucidated which derivatives that can bind more strongly to PLN and be putative antimicrobial agents capable of inhibiting the PLN activity.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1656672DOI Listing
July 2020

Change in binding states between catabolite activating protein and DNA induced by ligand-binding: molecular dynamics and ab initio fragment molecular orbital calculations.

J Mol Model 2019 Jun 16;25(7):192. Epub 2019 Jun 16.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan.

The transcription mechanism of genetic information from DNA to RNA is efficiently controlled by regulatory proteins, such as catabolite activator protein (CAP), and their ligands. When cyclic AMP (cAMP) binds to CAP, the complex forms a dimer and binds specifically to DNA to activate the transcription mechanism. On the other hand, when cyclic GMP (cGMP) binds to CAP, the complex has no marked effect on the mechanism. In our previous study, based on molecular dynamics (MD) and ab initio fragment molecular orbital (FMO) methods, we elucidated which residues of CAP are important for the specific interactions between CAP and DNA in the CAP-monomer+DNA + cAMP complex. However, this monomer model for CAP cannot describe real interactions between the CAP-dimer and DNA because CAPs form a dimer before binding to DNA. Accordingly, here, we investigated stable structures and their electronic states for the CAP-dimer+DNA complex with cAMP or cGMP ligand, to clarify the influence of ligand-binding on the interactions between CAP-dimer and DNA. The MD simulations elucidated that the DNA-binding domains of CAP-dimer behave differently depending on the ligand bound to the CAP-dimer. In addition, FMO calculations revealed that the binding energy between CAP-dimer and DNA for the CAP-dimer+DNA + cAMP complex is larger than that for the CAP-dimer+DNA + cGMP complex, being consistent with experiments. It was also highlighted that the Arg185 and Lys188 residues of CAP-dimer are important for the binding between CAP-dimer and DNA. These results provide useful information for proposing new compounds that efficiently control the transcription mechanism.
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http://dx.doi.org/10.1007/s00894-019-4087-3DOI Listing
June 2019

Specific interactions between 2-trans enoyl-acyl carrier protein reductase and its ligand: Protein-ligand docking and ab initio fragment molecular orbital calculations.

J Mol Graph Model 2019 05 25;88:299-308. Epub 2019 Feb 25.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan. Electronic address:

2-trans enoyl-acyl carrier protein reductase (InhA) has been identified as a promising target for the development of novel chemotherapy for tuberculosis. In the present study, a series of heteroaryl benzamide derivatives were selected as potent inhibitors against InhA, and their binding properties with InhA were investigated at atomic and electronic levels by ab initio molecular simulations based on protein-ligand docking, classical molecular mechanics optimizations and ab initio fragment molecular orbital (FMO) calculations. The results evaluated by FMO highlight some key interactions between InhA and the derivatives, indicating that the most potent derivative has strong hydrogen bonds with the Met98 side chain of InhA and strong electrostatic interactions with the nicotinamide adenine dinucleotide cofactor. These findings provide informative structural concepts for designing novel heteroaryl benzamide derivatives with higher binding affinity to InhA.
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http://dx.doi.org/10.1016/j.jmgm.2019.02.011DOI Listing
May 2019

Ligand chirality can affect histidine protonation of vitamin-D receptor: ab initio molecular orbital calculations in water.

J Steroid Biochem Mol Biol 2019 02 29;186:89-95. Epub 2018 Sep 29.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan. Electronic address:

Vitamin D is recognized to play important roles in the onset of immunological diseases as well as the regulation of the amount of Ca in the blood. Since these physiological actions caused by active vitamin D are triggered by the specific interaction between the vitamin D receptor (VDR) and active vitamin D, many types of compounds have been developed as potent ligands against VDR. It was found that the binding affinity between VDR and its ligand depends significantly on the chirality of the ligand. However, the reason for the dependence has, thus far, not been elucidated. In the present study, we investigated the specific interactions between VDR and some ligands with different chirality, using ab initio fragment molecular orbital (FMO) calculations. The FMO results reveal that two histidine residues of VDR contribute significantly to the binding between VDR and ligand and that their protonation states can affect the specific interactions between VDR and ligand. We therefore considered other possible protonation states of these histidine residues and determined their most stable states, using the ab initio FMO calculations. The results illustrate the possibility that the difference in the chirality of a ligand can induce the change in protonation states of the histidine residues of VDR existing near the ligand. This finding provides an important warning that the protonation states of histidine residues existing near the ligand should be considered more precisely in the molecular simulations for investigating the specific interactions between protein and ligand.
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http://dx.doi.org/10.1016/j.jsbmb.2018.09.020DOI Listing
February 2019

Proposal of potent inhibitors for vitamin-D receptor based on ab initio fragment molecular orbital calculations.

J Mol Graph Model 2018 03 31;80:320-326. Epub 2018 Jan 31.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan. Electronic address:

Vitamin D plays an important role in the regulation of the calcium and phosphorus metabolism as well as in bone formation. These physiological actions caused by vitamin D are triggered by the specific binding of vitamin D to its receptor (VDR). Here we investigated the specific interactions and binding affinities between VDR and vitamin D derivatives, using ab initio fragment molecular orbital (FMO) calculations. The FMO results elucidate that relative position of the two hydroxyl groups of the derivatives is essential for the strong binding affinity between the derivative and Arg274 residue of VDR. It is therefore expected that novel potent ligands, which have a great binding affinity for VDR, are developed by adjusting the positions of the hydroxyl groups in the derivatives in such a way as these groups form strong hydrogen bonds with VDR residues. We proposed these novel derivatives and investigated their specific interactions with VDR at atomic and electronic levels to obtain a more potent ligand for VDR.
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http://dx.doi.org/10.1016/j.jmgm.2018.01.014DOI Listing
March 2018

A novel peptide blocking cancer cell invasion by structure-based drug design.

Biomed Rep 2017 Sep 31;7(3):221-225. Epub 2017 Jul 31.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara 634-8522, Japan.

The receptor for the urokinase-type plasminogen activator (uPA), uPAR, facilitates tumor cell invasion and metastasis by focusing on several ligands, including uPA, integrins and vitronectin. With computational prediction algorithms and structure-based drug design, we identified peptides containing the Gly-Lys-Gly-Glu-Gly-Glu-Gly-Lys-Gly sequence (peptide H1), which strongly interacts with uPAR. The aim of the present study was to investigate the effect of allosteric inhibition at the uPAR interface using a novel synthetic peptide and its function on ovarian cancer cell invasion. The molecular and functional mechanisms of H1 were determined by complementary biochemical and biological methods in the promyeloid U937 cell line as well as ovarian cancer cell lines, including serous carcinoma SKOV3 and clear cell carcinoma TOV21G. The effects of H1 treatment on cancer cell invasion were evaluated . H1 inhibited cancer cell invasion, without affecting cell viability, accompanied by the suppression of extracellular signal-regulated kinase (ERK)-1 phosphorylation and then matrix metalloproteinase (MMP)-9 expression. H1 failed to block the interaction of uPA-uPAR protein-protein interaction in cells, but antagonized the uPA function. H1 failed to disrupt the uPA-uPAR complex, but abolished the invasion of ovarian cancer cells at least through suppression of the ERK-MMP-9 signaling pathway. Further studies are needed to confirm our observations and to describe the underlying molecular mechanism.
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http://dx.doi.org/10.3892/br.2017.957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547769PMC
September 2017

Specific interactions between androgen receptor and its ligand: ab initio molecular orbital calculations in water.

J Mol Graph Model 2017 08 13;75:383-389. Epub 2017 Jun 13.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan. Electronic address:

The Androgen Receptor (AR) is a family of nuclear receptor proteins and a ligand-activated transcription factor. Since its abnormal activation can cause the progression of prostate cancer, numerous types of antagonists against AR have been developed as promising agents for treating prostate cancers. We here investigated the specific interactions between AR and several types of non-steroid agents at an electronic level, using ab initio molecular simulations based on molecular mechanics and ab initio fragment molecular orbital (FMO) methods From the results obtained by FMO, we proposed novel agents as potent ligands against AR and investigated the binding properties between AR and these agents to confirm that some of them can bind more strongly with AR than the existing non-steroid agents and can be strongly effective ligands against AR.
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http://dx.doi.org/10.1016/j.jmgm.2017.06.003DOI Listing
August 2017

Specific interactions between zinc metalloproteinase and its inhibitors: Ab initio fragment molecular orbital calculations.

J Mol Graph Model 2017 08 8;75:277-286. Epub 2017 Jun 8.

Department of Computer Science and Engineering, Toyohashi University of Technology, Toyohashi, 441-8580, Japan. Electronic address:

Bacteria secrete the enzyme pseudolysin (PLN) to degrade exocellular proteins, and the produced peptides are used as a nutrient for the bacteria. It is thus expected that inhibition of PLN can suppress bacterial growth. Since such inhibitors do not attack to bacteria directly, the risk of producing drug-resistance bacteria is less. However, endogenous proteinases such as the matrix metalloproteinases (MMPs) have active site similar to that of PLN, and there is a possibility that PLN inhibitors also inhibit the activity of MMPs, resulting in a loss of substrate degradation by these proteinases. Therefore, agents that inhibit the activity of only PLN and not MMPs are required. In the present study, we select two compounds (ARP101 and LM2) and investigate their specific interactions with PLN and MMPs by use of ab initio molecular simulations. Based on the results, we propose several novel compounds as candidates for potent PLN inhibition and investigate their binding properties with PLN, elucidating that the compound, in which a toluene group is introduced into LM2, has larger binding energy with PLN compared with the pristine LM2. Therefore, this compound is suggested to be a potent PLN inhibitor.
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http://dx.doi.org/10.1016/j.jmgm.2017.05.013DOI Listing
August 2017

Specific interactions between vitamin-D receptor and its ligands: Ab initio molecular orbital calculations in water.

J Steroid Biochem Mol Biol 2017 07 27;171:75-79. Epub 2017 Feb 27.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan. Electronic address:

Vitamin D is recognized to play important roles not only in the bone metabolism and the regulation of Ca amount in the blood but also in the onset of immunological diseases. These physiological actions caused by vitamin D are triggered by the specific interaction between vitamin D receptor (VDR) and vitamin D. In the present study, we investigated the interactions between VDR and vitamin D derivatives using ab initio molecular simulation, in order to elucidate the reason for the significant difference in their effects on VDR activity. Based on the results simulated, we elucidated which parts of the derivatives and which residues of VDR mainly contribute to the specific binding between VDR and the derivatives at an electronic level. This finding will be helpful for proposing new vitamin D derivatives as a potent modulator or inhibitor against VDR.
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http://dx.doi.org/10.1016/j.jsbmb.2017.02.018DOI Listing
July 2017

Ab initio molecular simulations for proposing potent inhibitors to butyrylcholinesterases.

J Mol Graph Model 2014 Nov 18;54:54-61. Epub 2014 Sep 18.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Aichi 441-8580, Japan. Electronic address:

Butyrylcholinesterase (BChE) exists mainly at neuromuscular junctions and plays an important role in the hydrolyzing mechanism of neurotransmitter acetylcholine. A variety of compounds have been produced in order to inhibit the function of BChE. We here investigate the specific interactions between BChE and some ligands (Kx) with large binding affinity to BChE, using ligand-docking, classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods. The binding energies between BChE and Kx evaluated by the FMO method have a correlation with the 50% inhibition concentration obtained by the previous experiments. In addition, the FMO calculations highlight that Asp70, Trp82 and Tyr128 residues of BChE contribute significantly to the binding between BChE and Kx. Based on the results, we propose some novel ligands and elucidate that one of the proposed ligands can bind strongly to BChE. The present results are useful for developing potent inhibitors to BChE.
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http://dx.doi.org/10.1016/j.jmgm.2014.09.002DOI Listing
November 2014

Ab initio molecular simulations for proposing novel peptide inhibitors blocking the ligand-binding pocket of urokinase receptor.

J Mol Model 2014 Jun 25;20(6):2292. Epub 2014 May 25.

Department of Computer Science of Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan.

Recent biochemical experiments have revealed that a variety of proteases play important roles in cancer invasion and metastasis. Among these proteases, urokinase-type plasminogen activator (uPA) is particularly important, since its specific binding to the receptor (uPAR) existing on the surface of a cancer cell is considered to be a trigger for cancer invasion. It is thus expected that the blocking of the binding can inhibit cancer invasion in the cancer patients and improve their prognosis dramatically. To develop a potent inhibitor for the binding, many types of peptides of amino acids were produced and their effect on the cancer invasion was investigated in the previous biochemical experiments. On the other hand, our previous ab initio molecular simulations have clarified that some amino acid residues of uPA play important roles in the specific binding between uPA and uPAR. In the present study, we propose some peptides composed of these important residues and investigate the specific interactions and the binding affinity between uPAR and the peptides at an electronic level, using ab initio molecular simulations. Base on the results simulated, we elucidate which peptide can bind more strongly to uPAR and propose a novel potent peptide which can inhibit the binding between uPAR and uPA efficiently.
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http://dx.doi.org/10.1007/s00894-014-2292-7DOI Listing
June 2014

Effect of D23N mutation on the dimer conformation of amyloid β-proteins: ab initio molecular simulations in water.

J Mol Graph Model 2014 May 16;50:113-24. Epub 2014 Apr 16.

Department of Computer Science and Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan. Electronic address:

The molecular pathogenesis of Alzheimer's disease (AD) is deeply involved in aggregations of amyloid β-proteins (Aβ) in a diseased brain. The recent experimental studies indicated that the mutation of Asp23 by Asn (D23N) within the coding sequence of Aβ increases the risk for the pathogeny of cerebral amyloid angiopathy and early-onset familial ADs. Fibrils of the D23N mutated Aβs can form both parallel and antiparallel structures, and the parallel one is considered to be associated with the pathogeny. However, the structure and the aggregation mechanism of the mutated Aβ fibrils are not elucidated at atomic and electronic levels. We here investigated solvated structures of the two types of Aβ dimers, each of which is composed of the wild-type or the D23N mutated Aβ, using classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods, in order to reveal the effect of the D23N mutation on the structure of Aβ dimer as well as the specific interactions between the Aβ monomers. The results elucidate that the effect of the D23N mutation is significant for the parallel structure of Aβ dimer and that the solvating water molecules around the Aβ dimer have significant contribution to the stability of Aβ dimer.
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http://dx.doi.org/10.1016/j.jmgm.2014.03.004DOI Listing
May 2014

Attacking mechanism of hydroxyl radical to DNA base-pair: density functional study in vacuum and in water.

J Biomol Struct Dyn 2015 27;33(1):158-66. Epub 2014 Jan 27.

a Department of Computer Science and Engineering , Toyohashi University of Technology , Tempaku-cho, Toyohashi, Aichi 441 8580 , Japan.

Recently, the influence of radiation on human body has been recognized as a serious problem. In particular, highly reactive hydroxyl radicals *OH produced by the radiation react with DNA, resulting in a great damage on its structure and electronic properties. It is thus important to investigate the reaction mechanism of *OH to DNA for elucidating the initial damage in DNA induced by the radiation. In the present study, we search for transition states (TS) of the reaction between G-C/A-T base-pair and [Formula: see text] in vacuum and in water, by the density functional theory (DFT) calculations. At first, we obtain the stable structures for the dehydrogenated G-C and A-T, in which the hydrogen atom of NH2 group of G or A base is abstracted by [Formula: see text]. From the structures of the dehydrogenated as well as the natural base-pairs, the TS between these structures is searched for and the activation free energy (AFE) is estimated for the reaction. In vacuum, AFEs for the G-C and A-T are almost the same each other, while the stabilization energy by the reaction for G-C is about 4.9 kcal/mol larger than that for A-T, indicating that the population of the dehydrogenated G-C is remarkably larger than that of the dehydrogenated A-T in vacuum. On the other hand, in water approximated by the continuum solvation model, the AFE for A-T is 2.6 kcal/mol smaller than that for G-C, indicating that the reaction dehydrogenated by [Formula: see text] occurs more frequently for the solvated A-T base-pair than G-C.
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http://dx.doi.org/10.1080/07391102.2013.864572DOI Listing
January 2016

Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme.

Curr Top Med Chem 2012 ;12(16):1748-62

Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway.

Thermolysin (TLN) and other thermolysin-like zinc metalloproteinases (TLPs),are important virulence factors for pathogenesis of bacterial infections by suppressing the innate immune system of the host. Therapeutic inhibition ofTLPs is believed to be a novel strategy inthe development of a new generation antibiotics.In the present study inhibition of TLN and angiotensin I-converting enzyme (ACE) by small peptides were studied by in vitro binding assays and theoretical calculations. The capacity of the peptides to inhibitTLN induced cleavage ofthe transcription factor nuclear factor kappa beta (NF-κB) was studied by electrophoretic mobility shift assays (EMSAs).Nine peptides inhibited ACE with IC50 values in the range 0.48 (IVY) to 1408 (HF) μM, while seven inhibited TLN with IC50 values in the range 0.00034 (IY) to 95640 (FW) μM. Calculations indicated that the peptides occupied the S1' and S2' subsites of ACE, and that IY, LW and IW occupiedthe S1' and S2' subsites, while FW, WL and WV occupiedthe S1 and S1' subsites of TLN. EMSA showed that peptides inhibited TLN induced cleavage of NF-κB. The studied peptides may form as a basis for the design of new compoundstargeting TLN with a potential in the treatment of bacterial infections.
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http://dx.doi.org/10.2174/156802612803989246DOI Listing
June 2013

Structure-based analysis of the molecular recognitions between HIV-1 TAR-RNA and transcription factor nuclear factor-kappaB (NFkB).

Curr Top Med Chem 2012 ;12(8):814-27

Department of Biochemistry and Molecular Biology, Section of Molecular Biology, University of Ferrara, Via Fossato di Mortara 74, Ferrara I-44100, Italy.

In this paper we applied the "macromolecular docking" procedure to perform molecular modeling with the aim of screening transcription factor sequences for possible interaction to the HIV-1 TAR-RNA, employing the software Hex version 4.2. The molecular modeling data were compared with electrophoretic mobility shift assays (EMSA) and surface plasmon resonance (SPR) based biospecific interaction analysis (BIA) using an optical biosensor. Finally the specific interactions between NF-κB and RNA have been calculated utilizing the AMBER-MM and FMO calculations. The results obtained clearly indicate that (a) NF-kB p50 transcription factor can bind TAR-RNA; (b) this binding efficiency is lower than that displayed by NF-kB factor in respect to DNA sequences; (c) other structured RNAs used as controls do not bind to NF-kB; (d) TAR-RNA is capable to bind pre-formed NF-kB/DNA complexes. Despite the fact that our data do not indicate whether NF-kB/TAR-RNA complexes play a role in the early steps of HIV-1 transcriptional activation, the results presented strongly indicate that interactions between transcription factors recruited at the level of HIV-1 LTR might interact with the TAR-RNA and deserve further studies aimed to determine its role in the HIV-1 life cycle.
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http://dx.doi.org/10.2174/156802612800166800DOI Listing
October 2012

Specific interactions and binding energies between thermolysin and potent inhibitors: molecular simulations based on ab initio molecular orbital method.

J Mol Graph Model 2012 Mar 2;33:1-11. Epub 2011 Nov 2.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Aichi, Japan.

Biochemical functions of the metalloprotease thermolysin (TLN) are controlled by various inhibitors. In a recent study we identified 12 compounds as TLN inhibitors by virtual screening and in vitro competitive binding assays. However, the specific interactions between TLN and these inhibitors have not been clarified. We here investigate stable structures of the solvated TLN-inhibitor complexes by classical molecular mechanics simulations and elucidate the specific interactions between TLN and these inhibitors at an electronic level by using ab initio fragment molecular orbital (FMO) calculations. The calculated binding energies between TLN and the inhibitors are qualitatively consistent with the experimental results, and the FMO results elucidate important amino acid residues of TLN for inhibitor binding. Based on the calculated results, we propose a novel potent inhibitor having a large binding affinity to TLN.
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http://dx.doi.org/10.1016/j.jmgm.2011.10.006DOI Listing
March 2012

Specific interactions and binding free energies between thermolysin and dipeptides: molecular simulations combined with ab initio molecular orbital and classical vibrational analysis.

J Comput Chem 2011 Nov 3;32(14):3047-57. Epub 2011 Aug 3.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Aichi 441-8580, Japan.

Thermolysin (TLN) is a metalloprotease widely used as a nonspecific protease for sequencing peptide and synthesizing many useful chemical compounds by the chemical industry. It was experimentally shown that the activity and functions of TLN are inhibited by the binding of many types of amino acid dipeptides. However, the binding mechanisms between TLN and dipeptides have not been clarified at the atomic and electronic levels. In this study, we investigated the binding mechanisms between TLN and four dipeptides. Specific interactions and binding free energies (BFEs) between TLN and the dipeptides were calculated using molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital (FMO) methods. The molecular systems were embedded in solvating water molecules during calculations. The calculated BFEs were qualitatively consistent with the trend of the experimentally observed inhibition of TLN activity by binding of the dipeptides. In addition, the specific interactions between the dipeptides and each amino acid residue of TLN or solvating water molecules were elucidated by the FMO calculations.
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http://dx.doi.org/10.1002/jcc.21887DOI Listing
November 2011

The effects of amino-acid mutations on specific interactions between urokinase-type plasminogen activator and its receptor: Ab initio molecular orbital calculations.

J Mol Graph Model 2011 Aug 16;29(8):975-84. Epub 2011 Apr 16.

Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan.

During cancer invasion, the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on the surface of a cancer cell is considered a trigger for invasion. Here, we present a stable structure of the solvated complex formed between uPA and uPAR (uPA-uPAR) and investigate the specific interactions between uPA and uPAR by ab initio fragment molecular orbital (FMO) calculations. The result indicates that the electrostatic interactions between the charged amino acid residues existing in both uPA and uPAR make a large contribution to the binding between uPA and uPAR. In particular, Lys23, Lys46, Lys98 and Lys61 of uPA are found to have strong attractive interactions with uPAR. To elucidate the effect of these residues on the interactions between uPA and uPAR, we substituted each of them with the uncharged amino acid Leu and investigated the interactions between the mutated uPA and wild-type uPAR. The interaction energies indicate that Lys46 and Lys98, which bind uPA to the rim of the central ligand-binding cavity of uPAR, make greater contributions to the binding between uPA and uPAR than Lys23, which is positioned at the bottom of the ligand-binding cavity of uPAR. The effect of hydrating water molecules located between uPA and uPAR is also investigated to be significant for the specific interactions between uPA and uPAR. These results are expected to be informative for developing new peptide antagonists that block the binding of uPA to uPAR.
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http://dx.doi.org/10.1016/j.jmgm.2011.04.003DOI Listing
August 2011

Specific interactions between lactose repressor protein and DNA affected by ligand binding: ab initio molecular orbital calculations.

J Comput Chem 2011 Jun 15;32(8):1661-70. Epub 2011 Feb 15.

Department of Computer Science and Engineering, Toyohashi University of Technology, Toyohashi, Aichi 441-8580, Japan.

Transcription mechanisms of gene information from DNA to mRNA are essentially controlled by regulatory proteins such as a lactose repressor (LacR) protein and ligand molecules. Biochemical experiments elucidated that a ligand binding to LacR drastically changes the mechanism controlled by LacR, although the effect of ligand binding has not been clarified at atomic and electronic levels. We here investigated the effect of ligand binding on the specific interactions between LacR and operator DNA by the molecular simulations combined with classical molecular mechanics and ab initio fragment molecular orbital methods. The results indicate that the binding of anti-inducer ligand strengthens the interaction between LacR and DNA, which is consistent with the fact that the binding of anti-inducer enhances the repression of gene transcription by LacR. It was also elucidated that hydrating water molecules existing between LacR and DNA contribute to the specific interactions between LacR and DNA.
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http://dx.doi.org/10.1002/jcc.21744DOI Listing
June 2011

Specific interactions between aryl hydrocarbon receptor and dioxin congeners: ab initio fragment molecular orbital calculations.

J Mol Graph Model 2010 Sep 25;29(2):197-205. Epub 2010 Jun 25.

Department of Knowledge-based Information Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan.

Aryl hydrocarbon receptor (AhR) is a transcription factor and its function is activated by the binding of halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,4-trichlorodibenzo-p-dioxin (TrCDD). TCDD is highly toxic to rat, whereas its congener TrCDD shows only a weak effect on gene expression. In order to elucidate the reason of this remarkable difference in the effect of TCDD and TrCDD, we here obtained stable structures of the complexes with rat AhR (rAhR) and TCDD/TrCDD and investigated their electronic properties by using the ab initio fragment molecular orbital (FMO) method. The results indicate that TCDD binds more strongly to rAhR than TrCDD, which is consistent with the experimentally observed toxicity of TCDD and TrCDD. Furthermore, ab initio FMO calculations elucidate that His324 and Gln381 of rAhR are important for binding TCDD, while His324 and Ser334 are important for TrCDD binding.
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http://dx.doi.org/10.1016/j.jmgm.2010.06.008DOI Listing
September 2010

A combined DFT/Green's function study on electrical conductivity through DNA duplex between Au electrodes.

Chem Phys Lett 2009 Jun;474(4):362-365

Department of Knowledge-based Information Engineering, Toyohashi University of Technology, Tenpaku-cho, Toyohashi, Aichi 441-8580, Japan.

Electrical conducting properties of DNA duplexes sandwiched between Au electrodes have been investigated by use of first-principles molecular simulation based on DFT and Green's function to elucidate the origin of their base sequence dependence. The theoretically simulated effects of DNA base sequence on the electrical conducting properties are in qualitative agreement with experiment. The HOMOs localized on Guanine bases have the major contribution to the electrical conductivity through DNA duplexes.
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http://dx.doi.org/10.1016/j.cplett.2009.04.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761638PMC
June 2009

Ab initio molecular orbital calculations on specific interactions between urokinase-type plasminogen activator and its receptor.

J Mol Graph Model 2009 Aug 9;28(1):46-53. Epub 2009 Apr 9.

Department of Knowledge-based Information Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi, 441-8580, Japan.

Cancer invasions and metastases are controlled by various proteases. In particular, the binding of urokinase-type plasminogen activator (uPA) to the uPA receptor (uPAR) existing on the surface of cancer cell is considered to be a trigger for cancer invasions. In the present study, we determined the structure of uPA and uPAR complex in water and investigated the specific interactions between uPA and uPAR by ab initio molecular orbital (MO) calculations based on fragment MO method. The result indicates that the 20-26 amino acid residues of uPA are important for the binding between uPA and uPAR, and that the electrostatic interactions between the charged amino acid residues existing in both uPA and uPAR have large contribution to the binding. The influence of crystal water molecules existing between uPA and uPAR was also investigated to be significant on the specific interactions between uPA and uPAR. These results are expected to be informative for developing new medicines blocking the binding of uPA and uPAR.
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http://dx.doi.org/10.1016/j.jmgm.2009.04.001DOI Listing
August 2009
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