Shuichi Miyamoto - Academia.edu (original) (raw)

Papers by Shuichi Miyamoto

Molecules, Nov 16, 2020

Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molec... more Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molecular transport, the rate of which is governed mainly by the diffusion coefficient; however, few coefficients are available because the measurement of diffusion rates is not straightforward. The translational diffusion coefficient is related by the Stokes-Einstein equation to the approximate radius of the diffusing molecule. Therefore, the stable conformations of small molecules were first calculated by molecular modeling. A simple radius r s and an effective radius r e were then proposed and estimated using the stable conformers with the van der Waals radii of atoms. The diffusion coefficients were finally calculated with the Stokes-Einstein equation. The results showed that, for the molecules with strong hydration ability, the diffusion coefficients are best given by r e and for other compounds, r s provided the best coefficients, with a reasonably small deviation of~0.3 × 10 −6 cm 2 /s from the experimental data. This demonstrates the effectiveness of the theoretical estimation approach, suggesting that diffusion coefficients have potential use as an additional molecular property in drug screening.

Chem-bio Informatics Journal, Apr 30, 2022

Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molec... more Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molecular transport, the rate of which is governed mainly by the diffusion coefficient; however, few coefficients are available for small molecules. We have constructed a simple and convenient experimental system with agar-gel to measure the diffusion coefficients of sugars. A theoretical method has also been developed to estimate diffusion coefficients by a combination of molecular modeling and the Stokes-Einstein equation, by which the coefficients of several sugars, amino acids, and drug molecules have been obtained. This time we have applied both experimental and theoretical approaches to estimate the diffusion coefficients of an additional 10 amino acids. The measured and calculated values are consistent with small deviations, i.e., the diffusion coefficients estimated by molecular modeling correspond well to the experimental data, which suggests that the potential use of the diffusion coefficient as an additional molecular property in drug screening has been enhanced.

Chem-Bio Informatics Journal, 2001

Some pyridyl-pyrrole compounds were found to have inhibitory activities against p38 MAP kinase. T... more Some pyridyl-pyrrole compounds were found to have inhibitory activities against p38 MAP kinase. Their activity was much more potent than that of SB203580 that has a similar overall structure but with a different core group, i.e., an imidazole ring. The complex structure modeling was therefore carried out in an attempt to obtain insights into the interactions of the kinase with the pyridyl-pyrrole compounds and SB203580. The resultant complex models revealed that the imidazole and the pyrrole compounds had similar binding modes and that the representative interactions between the enzyme and the ligand moiety (pyridyl or phenyl) were common. For the sulfoxy moiety including the aliphatic tethers attached to a terminal functional group, the amino acid residues interacting with the moiety were elucidated. Lastly, the affinities of the inhibitors were estimated by calculating the score values with the Ludi program and a good correlation between the p38 MAP kinase inhibitory activities and the score values was found.

Chem-Bio Informatics Journal, 2009

The stability, dispersibility and oral bioavailability of coenzyme Q10 (CoQ10) are known to be im... more The stability, dispersibility and oral bioavailability of coenzyme Q10 (CoQ10) are known to be improved upon complexing CoQ10 with -cyclodextrin (-CD). However, the details of the three-dimensional structure of the -CD/CoQ10 complex are not well understood. Therefore, the molecular composition and three-dimensional structure of the complex were investigated using chemical analyses and molecular modeling. The molecular ratio of -CD and CoQ10 in the complex was investigated by NMR as well as by HPLC to determine the -CD/CoQ10 ratio of 2.5. DSC analysis of the -CD/CoQ10 complex indicated formation of the inclusion complex. Three different complex models (-CDx2+CoQ10; -CDx3+CoQ10; -CDx5+CoQ10x2) that correspond to the derived -CD/CoQ10 ratio were also constructed and then molecular mechanics and dynamics calculations were carried out to provide several possible complex structures. Based on the complex structures thus obtained, structural and energetic features of the complexes were examined.

Journal of Molecular Graphics and Modelling, 2000

A conformational analysis and docking study of nitrophenoxyalkylbenzylamine derivatives with inhi... more A conformational analysis and docking study of nitrophenoxyalkylbenzylamine derivatives with inhibitory activities against acethylcholinesterase was carried out in an attempt to analyze their structureactivity relationships based on the enzymeinhibitor interaction. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by molecular dynamics. Next, a docking study of the inhibitors into the ligand binding site was performed. Among the resulting stable complex structures, it was found that in the case of the two stereoisomers with a 7-membered ring, the more active one of the two formed a much more stable complex structure. On the other hand, complex structures with comparable energies were obtained for both stereoisomers that had no 7-membered ring and showed similar inhibitory activities. Lastly, structural features of the complex models of a series of inhibitors with side chains of different lengths were evaluated and corresponded well to their inhibitory activities.

Crystal Structure Theory and Applications, 2013

Exodeoxyribonuclease III (EXOIII) acts as a 3'→5' exonuclease and is homologous to purinic/apyrim... more Exodeoxyribonuclease III (EXOIII) acts as a 3'→5' exonuclease and is homologous to purinic/apyrimidinic (AP) endonuclease (APE), which plays an important role in the base excision repair pathway. To structurally investigate the reaction and substrate recognition mechanisms of EXOIII, a crystallographic study of EXOIII from Sulfolobus tokodaii strain 7 was carried out. The purified enzyme was crystallized by using the hanging-drop vapor-diffusion method. The crystals belonged to space group C2, with unit-cell parameters a = 154.2, b = 47.7, c = 92.4 Å, β = 125.8˚ and diffracted to 1.5 Å resolution.

Molecules, 2020

Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molec... more Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molecular transport, the rate of which is governed mainly by the diffusion coefficient; however, few coefficients are available because the measurement of diffusion rates is not straightforward. The translational diffusion coefficient is related by the Stokes–Einstein equation to the approximate radius of the diffusing molecule. Therefore, the stable conformations of small molecules were first calculated by molecular modeling. A simple radius rs and an effective radius re were then proposed and estimated using the stable conformers with the van der Waals radii of atoms. The diffusion coefficients were finally calculated with the Stokes–Einstein equation. The results showed that, for the molecules with strong hydration ability, the diffusion coefficients are best given by re and for other compounds, rs provided the best coefficients, with a reasonably small deviation of ~0.3 × 10−6 cm2/s from ...

Chemical and Pharmaceutical Bulletin, 2018

The isolation of useful microbes is one of the traditional approaches for the lead generation in ... more The isolation of useful microbes is one of the traditional approaches for the lead generation in drug discovery. As an effective technique for microbe isolation, we recently developed a multidimensional diffusionbased gradient culture system of microbes. In order to enhance the utility of the system, it is favorable to have diffusion coefficients of nutrients such as sugars in the culture medium beforehand. We have, therefore, built a simple and convenient experimental system that uses agar-gel to observe diffusion. Next, we performed computer simulations-based on random-walk concepts-of the experimental diffusion system and derived correlation formulas that relate observable diffusion data to diffusion coefficients. Finally, we applied these correlation formulas to our experimentally-determined diffusion data to estimate the diffusion coefficients of sugars. Our values for these coefficients agree reasonably well with values published in the literature. The effectiveness of our simple technique, which has elucidated the diffusion coefficients of some molecules which are rarely reported (e.g., galactose, trehalose, and glycerol) is demonstrated by the strong correspondence between the literature values and those obtained in our experiments.

Journal of Pharmaceutical Sciences, 2017

Sodium 4-phenylbutyrate (PB) is clinically used as a drug for treating urea cycle disorders. Rece... more Sodium 4-phenylbutyrate (PB) is clinically used as a drug for treating urea cycle disorders. Recent research has shown that PB also has other pharmacologic activities, suggesting that it has the potential for use as a drug for treating other disorders. In the process of drug development, preclinical testing using experimental animals is necessary to verify the efficacy and safety of PB. Although the binding of PB to human albumin has been studied, our knowledge of its binding to albumin from the other animal species is extremely limited. To address this issue, we characterized the binding of PB to albumin from several species (human, bovine, rabbit, and rat). The results indicated that PB interacts with 1 high-affinity site of albumin from these species, which corresponds to site II of human albumin. The affinities of PB to human and bovine albumins were higher than those to rabbit and rat albumin, and that to rabbit albumin was the lowest. Binding and molecular docking studies using structurally related compounds of PB suggested that species differences in the affinity are attributed to differences in the structural feature of the PB-binding sites on albumins (e.g., charge distribution, hydrophobicity, shape, or size).

FEBS letters, Jan 14, 2015

Uracil-DNA glycosylases (UDGs) excise uracil from DNA by catalyzing the N-glycosidic bond hydroly... more Uracil-DNA glycosylases (UDGs) excise uracil from DNA by catalyzing the N-glycosidic bond hydrolysis. Here we report the first crystal structures of an archaeal UDG (stoUDG). Compared with other UDGs, stoUDG has a different structure of the leucine-intercalation loop, which is important for DNA binding. The stoUDG-DNA complex model indicated that Leu169, Tyr170, and Asn171 in the loop are involved in DNA intercalation. Mutational analysis showed that Tyr170 is critical for substrate DNA recognition. These results indicate that Tyr170 occupies the intercalation site formed after the structural change of the leucine-intercalation loop required for the catalysis.

Chem-Bio Informatics Journal, 2001

Three-dimensional models of the gelatinase catalytic domains were built from collagenase structur... more Three-dimensional models of the gelatinase catalytic domains were built from collagenase structures by the homology modeling technique. The docking of different types of inhibitors was then studied in an attempt to obtain structural insight into their binding modes. In the case of an amide compound docked with gelatinase A, almost the same binding mode was obtained as that observed in the crystal structure of another amide compound complexed with collagenase. With respect to our series of matlystatin analogs, the key hydrogen bonding and hydrophobic interactions with gelatinase B were similar to those of the above amide compounds, although these derivatives have a unique piperazine ring. The length and hydrophobic nature of the S1' subsite was well consistent with the observation that the inhibitory activity rises as the alkyl chain at P1' becomes longer. The binding mode of a sulfonamide inhibitor was slightly different from that of amide and piperazine inhibitors, but similar to that proposed recently for another sulfonamide inhibitor.

Drug Design and Discovery, 2003

Globomycin (1), a 19-membered cyclic depsipeptide, exhibited an antibiotic activity against gram-... more Globomycin (1), a 19-membered cyclic depsipeptide, exhibited an antibiotic activity against gram-negative bacteria by inhibiting signal peptidase II in the cytoplasmic membrane. Although only one conformation of 1 was observed for the crystal structure, it was revealed by 1H NMR spectroscopic analysis that 1 exists as a mixture of two rotational isomers in solution (CDCl3 and CD3OD). A conformational analysis of 1 was, therefore, performed by high-temperature molecular dynamics simulation in combination with 1H NMR analysis to elucidate the conformations in solution. The relative ratio of the major and minor isomers present, which differs depending on the solvent, was then derived from their relative energy differences obtained in the conformational analysis. The difference in the relative ratios corresponded with that calculated from the 1H NMR analysis. Finally, the predicted conformations in solution were compared with that of the X-ray crystal structure to find local and global differences that characterize these conformations.

Drug design and discovery, 2001

Aldose reductase has been implicated in the etiology of diabetic complications. Due to the limite... more Aldose reductase has been implicated in the etiology of diabetic complications. Due to the limited number of currently available drugs for the treatment of diabetic complications, we have carried out a structure-based de novo design and synthesis in an attempt to identify new aldose reductase inhibitors. With the LEGEND program, we have designed 200 chemical structures that fit into the ligand binding site of the crystal structure of the enzyme. After their visual inspection and assessment of synthetic feasibility, four compounds were chosen to be synthesized. These compounds were all found to have reasonable inhibitory activities (IC50 = 17-91 microM), indicating the first successful generation of nonpeptide drug leads that have been obtained using a rational de novo design approach.

Peptide Chemistry 1992, 1993

Real-time outdoor navigation in highly dynamic environments is an crucial problem. The recent lit... more Real-time outdoor navigation in highly dynamic environments is an crucial problem. The recent literature on real-time static SLAM don't scale up to dynamic outdoor environments. Most of these methods assume moving objects as outliers or discard the information provided by them. We propose an algorithm to jointly infer the camera trajectory and the moving object trajectory simultaneously. In this paper, we perform a sparse scene flow based motion segmentation using a stereo camera. The segmented objects motion models are used for accurate localization of the camera trajectory as well as the moving objects. We exploit the relationship between moving objects for improving the accuracy of the poses. We formulate the poses as a factor graph incorporating all the constraints. We achieve exact incremental solution by solving a full nonlinear optimization problem in real time. The evaluation is performed on the challenging KITTI dataset with multiple moving cars.Our method outperforms the previous baselines in outdoor navigation.

Proteins: Structure, Function, and Genetics, 1993

We present calculations of the absolute and relative binding free energies of complexation of str... more We present calculations of the absolute and relative binding free energies of complexation of streptavidin with biotin and its analogs by means of a thermodynamic free energy perturbation method implemented with molecular dynamics. Using the recently solved crystal structure of the streptavidin-biotin complex, biotin was mutated into a dummy molecule as well as thiobiotin and iminobiotin both in the protein and in solution. The calculated absolute binding free energy was dependent on the simulation model used. Encouragingly, the "best models" provided a reasonable semiquantitative reproduction (-20 to-22 kcallmol)

Proceedings of the National Academy of Sciences, 1993

Free energy perturbation methods using molecular dynamics have been used to calculate the absolut... more Free energy perturbation methods using molecular dynamics have been used to calculate the absolute free energy of association of two ligand-protein complexes. The calculations reproduce the significantly more negative free energy of association of biotin to streptavidin, compared to N-L-acetyltryptophanamide/alpha-chymotrypsin. This difference in free energy of association is due to van der Waals/dispersion effects in the nearly ideally performed cavity that streptavidin presents to biotin, which involves four tryptophan residues.

Journal of Theoretical Biology, 1982

Recent studies (Ohtsuki, 1979, 1980) have shown that troponin T (tropomysin binding component of ... more Recent studies (Ohtsuki, 1979, 1980) have shown that troponin T (tropomysin binding component of troponin complex) is a rod-shaped molecule of approximately 9 nm in length and associated with filamentous tropomyosin. The region of residues 90 to 148 of troponin T, which has been confirmed as a main portion of helix-rich fragment which strongly binds to tropomyosin (Jackson, Amphlett & Perry, 1975, Pearlstone & Smillie, 1977), was predicted as a long stretch of a-helix by the method of secondary structure prediction (Nagano, 1977, Nagano et al., 1980). This paper deals with the mechanism of the specific binding explored by the extension of the method of schematic representation of helical interactions developed by McLachlan & Stewart (1976a) and, also, the method of scoring interactions of the staggered structures of collagen triplestranded coiled-coils developed by Hulmes et al. (1973). One of the most feasible structures of the specific binding complex was obtained as a triple-stranded coiled-coil made between a tropomyosin coiled-coil and the helical region of the specific binding fragment of troponin T, and confirmed by both LabQuip type and computer model building techniques. The techniques developed in the present work will be useful in elucidating the regulating mechanism of muscle contraction in its atomic details. The procedures and the steps for restricting the number of possible structures are outlined in Table 4.

Journal of the American Chemical Society, 2000

Journal of Synthetic Organic Chemistry, Japan, 1984

Journal of Medicinal Chemistry, 1987

alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic ... more alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic acids (monoester monoacids) and their dicarboxylic acids having the hydrophobic substituents at the 2- or 3-position of the thiazepinone ring were prepared and assayed for angiotensin-converting enzyme (ACE) inhibitory activity. The dicarboxylic acids having the pseudoequatorial amino groups at the 6-position and the pseudoequatorial hydrophobic substituents at the 2- or 3-position of the chair conformation of the thiazepinone ring had potent in vitro inhibitory activity. The monoester monoacids having the hydrophobic substituents at the 2-position suppressed pressor response to angiotensin I for a longer duration than those having the substituents at the 3-position when administered orally. The structure-activity relationship was studied by conformational energy calculations of the thiazepinone ring.

Molecules, Nov 16, 2020

Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molec... more Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molecular transport, the rate of which is governed mainly by the diffusion coefficient; however, few coefficients are available because the measurement of diffusion rates is not straightforward. The translational diffusion coefficient is related by the Stokes-Einstein equation to the approximate radius of the diffusing molecule. Therefore, the stable conformations of small molecules were first calculated by molecular modeling. A simple radius r s and an effective radius r e were then proposed and estimated using the stable conformers with the van der Waals radii of atoms. The diffusion coefficients were finally calculated with the Stokes-Einstein equation. The results showed that, for the molecules with strong hydration ability, the diffusion coefficients are best given by r e and for other compounds, r s provided the best coefficients, with a reasonably small deviation of~0.3 × 10 −6 cm 2 /s from the experimental data. This demonstrates the effectiveness of the theoretical estimation approach, suggesting that diffusion coefficients have potential use as an additional molecular property in drug screening.

Chem-bio Informatics Journal, Apr 30, 2022

Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molec... more Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molecular transport, the rate of which is governed mainly by the diffusion coefficient; however, few coefficients are available for small molecules. We have constructed a simple and convenient experimental system with agar-gel to measure the diffusion coefficients of sugars. A theoretical method has also been developed to estimate diffusion coefficients by a combination of molecular modeling and the Stokes-Einstein equation, by which the coefficients of several sugars, amino acids, and drug molecules have been obtained. This time we have applied both experimental and theoretical approaches to estimate the diffusion coefficients of an additional 10 amino acids. The measured and calculated values are consistent with small deviations, i.e., the diffusion coefficients estimated by molecular modeling correspond well to the experimental data, which suggests that the potential use of the diffusion coefficient as an additional molecular property in drug screening has been enhanced.

Chem-Bio Informatics Journal, 2001

Some pyridyl-pyrrole compounds were found to have inhibitory activities against p38 MAP kinase. T... more Some pyridyl-pyrrole compounds were found to have inhibitory activities against p38 MAP kinase. Their activity was much more potent than that of SB203580 that has a similar overall structure but with a different core group, i.e., an imidazole ring. The complex structure modeling was therefore carried out in an attempt to obtain insights into the interactions of the kinase with the pyridyl-pyrrole compounds and SB203580. The resultant complex models revealed that the imidazole and the pyrrole compounds had similar binding modes and that the representative interactions between the enzyme and the ligand moiety (pyridyl or phenyl) were common. For the sulfoxy moiety including the aliphatic tethers attached to a terminal functional group, the amino acid residues interacting with the moiety were elucidated. Lastly, the affinities of the inhibitors were estimated by calculating the score values with the Ludi program and a good correlation between the p38 MAP kinase inhibitory activities and the score values was found.

Chem-Bio Informatics Journal, 2009

The stability, dispersibility and oral bioavailability of coenzyme Q10 (CoQ10) are known to be im... more The stability, dispersibility and oral bioavailability of coenzyme Q10 (CoQ10) are known to be improved upon complexing CoQ10 with -cyclodextrin (-CD). However, the details of the three-dimensional structure of the -CD/CoQ10 complex are not well understood. Therefore, the molecular composition and three-dimensional structure of the complex were investigated using chemical analyses and molecular modeling. The molecular ratio of -CD and CoQ10 in the complex was investigated by NMR as well as by HPLC to determine the -CD/CoQ10 ratio of 2.5. DSC analysis of the -CD/CoQ10 complex indicated formation of the inclusion complex. Three different complex models (-CDx2+CoQ10; -CDx3+CoQ10; -CDx5+CoQ10x2) that correspond to the derived -CD/CoQ10 ratio were also constructed and then molecular mechanics and dynamics calculations were carried out to provide several possible complex structures. Based on the complex structures thus obtained, structural and energetic features of the complexes were examined.

Journal of Molecular Graphics and Modelling, 2000

A conformational analysis and docking study of nitrophenoxyalkylbenzylamine derivatives with inhi... more A conformational analysis and docking study of nitrophenoxyalkylbenzylamine derivatives with inhibitory activities against acethylcholinesterase was carried out in an attempt to analyze their structureactivity relationships based on the enzymeinhibitor interaction. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by molecular dynamics. Next, a docking study of the inhibitors into the ligand binding site was performed. Among the resulting stable complex structures, it was found that in the case of the two stereoisomers with a 7-membered ring, the more active one of the two formed a much more stable complex structure. On the other hand, complex structures with comparable energies were obtained for both stereoisomers that had no 7-membered ring and showed similar inhibitory activities. Lastly, structural features of the complex models of a series of inhibitors with side chains of different lengths were evaluated and corresponded well to their inhibitory activities.

Crystal Structure Theory and Applications, 2013

Exodeoxyribonuclease III (EXOIII) acts as a 3'→5' exonuclease and is homologous to purinic/apyrim... more Exodeoxyribonuclease III (EXOIII) acts as a 3'→5' exonuclease and is homologous to purinic/apyrimidinic (AP) endonuclease (APE), which plays an important role in the base excision repair pathway. To structurally investigate the reaction and substrate recognition mechanisms of EXOIII, a crystallographic study of EXOIII from Sulfolobus tokodaii strain 7 was carried out. The purified enzyme was crystallized by using the hanging-drop vapor-diffusion method. The crystals belonged to space group C2, with unit-cell parameters a = 154.2, b = 47.7, c = 92.4 Å, β = 125.8˚ and diffracted to 1.5 Å resolution.

Molecules, 2020

Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molec... more Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molecular transport, the rate of which is governed mainly by the diffusion coefficient; however, few coefficients are available because the measurement of diffusion rates is not straightforward. The translational diffusion coefficient is related by the Stokes–Einstein equation to the approximate radius of the diffusing molecule. Therefore, the stable conformations of small molecules were first calculated by molecular modeling. A simple radius rs and an effective radius re were then proposed and estimated using the stable conformers with the van der Waals radii of atoms. The diffusion coefficients were finally calculated with the Stokes–Einstein equation. The results showed that, for the molecules with strong hydration ability, the diffusion coefficients are best given by re and for other compounds, rs provided the best coefficients, with a reasonably small deviation of ~0.3 × 10−6 cm2/s from ...

Chemical and Pharmaceutical Bulletin, 2018

The isolation of useful microbes is one of the traditional approaches for the lead generation in ... more The isolation of useful microbes is one of the traditional approaches for the lead generation in drug discovery. As an effective technique for microbe isolation, we recently developed a multidimensional diffusionbased gradient culture system of microbes. In order to enhance the utility of the system, it is favorable to have diffusion coefficients of nutrients such as sugars in the culture medium beforehand. We have, therefore, built a simple and convenient experimental system that uses agar-gel to observe diffusion. Next, we performed computer simulations-based on random-walk concepts-of the experimental diffusion system and derived correlation formulas that relate observable diffusion data to diffusion coefficients. Finally, we applied these correlation formulas to our experimentally-determined diffusion data to estimate the diffusion coefficients of sugars. Our values for these coefficients agree reasonably well with values published in the literature. The effectiveness of our simple technique, which has elucidated the diffusion coefficients of some molecules which are rarely reported (e.g., galactose, trehalose, and glycerol) is demonstrated by the strong correspondence between the literature values and those obtained in our experiments.

Journal of Pharmaceutical Sciences, 2017

Sodium 4-phenylbutyrate (PB) is clinically used as a drug for treating urea cycle disorders. Rece... more Sodium 4-phenylbutyrate (PB) is clinically used as a drug for treating urea cycle disorders. Recent research has shown that PB also has other pharmacologic activities, suggesting that it has the potential for use as a drug for treating other disorders. In the process of drug development, preclinical testing using experimental animals is necessary to verify the efficacy and safety of PB. Although the binding of PB to human albumin has been studied, our knowledge of its binding to albumin from the other animal species is extremely limited. To address this issue, we characterized the binding of PB to albumin from several species (human, bovine, rabbit, and rat). The results indicated that PB interacts with 1 high-affinity site of albumin from these species, which corresponds to site II of human albumin. The affinities of PB to human and bovine albumins were higher than those to rabbit and rat albumin, and that to rabbit albumin was the lowest. Binding and molecular docking studies using structurally related compounds of PB suggested that species differences in the affinity are attributed to differences in the structural feature of the PB-binding sites on albumins (e.g., charge distribution, hydrophobicity, shape, or size).

FEBS letters, Jan 14, 2015

Uracil-DNA glycosylases (UDGs) excise uracil from DNA by catalyzing the N-glycosidic bond hydroly... more Uracil-DNA glycosylases (UDGs) excise uracil from DNA by catalyzing the N-glycosidic bond hydrolysis. Here we report the first crystal structures of an archaeal UDG (stoUDG). Compared with other UDGs, stoUDG has a different structure of the leucine-intercalation loop, which is important for DNA binding. The stoUDG-DNA complex model indicated that Leu169, Tyr170, and Asn171 in the loop are involved in DNA intercalation. Mutational analysis showed that Tyr170 is critical for substrate DNA recognition. These results indicate that Tyr170 occupies the intercalation site formed after the structural change of the leucine-intercalation loop required for the catalysis.

Chem-Bio Informatics Journal, 2001

Three-dimensional models of the gelatinase catalytic domains were built from collagenase structur... more Three-dimensional models of the gelatinase catalytic domains were built from collagenase structures by the homology modeling technique. The docking of different types of inhibitors was then studied in an attempt to obtain structural insight into their binding modes. In the case of an amide compound docked with gelatinase A, almost the same binding mode was obtained as that observed in the crystal structure of another amide compound complexed with collagenase. With respect to our series of matlystatin analogs, the key hydrogen bonding and hydrophobic interactions with gelatinase B were similar to those of the above amide compounds, although these derivatives have a unique piperazine ring. The length and hydrophobic nature of the S1' subsite was well consistent with the observation that the inhibitory activity rises as the alkyl chain at P1' becomes longer. The binding mode of a sulfonamide inhibitor was slightly different from that of amide and piperazine inhibitors, but similar to that proposed recently for another sulfonamide inhibitor.

Drug Design and Discovery, 2003

Globomycin (1), a 19-membered cyclic depsipeptide, exhibited an antibiotic activity against gram-... more Globomycin (1), a 19-membered cyclic depsipeptide, exhibited an antibiotic activity against gram-negative bacteria by inhibiting signal peptidase II in the cytoplasmic membrane. Although only one conformation of 1 was observed for the crystal structure, it was revealed by 1H NMR spectroscopic analysis that 1 exists as a mixture of two rotational isomers in solution (CDCl3 and CD3OD). A conformational analysis of 1 was, therefore, performed by high-temperature molecular dynamics simulation in combination with 1H NMR analysis to elucidate the conformations in solution. The relative ratio of the major and minor isomers present, which differs depending on the solvent, was then derived from their relative energy differences obtained in the conformational analysis. The difference in the relative ratios corresponded with that calculated from the 1H NMR analysis. Finally, the predicted conformations in solution were compared with that of the X-ray crystal structure to find local and global differences that characterize these conformations.

Drug design and discovery, 2001

Aldose reductase has been implicated in the etiology of diabetic complications. Due to the limite... more Aldose reductase has been implicated in the etiology of diabetic complications. Due to the limited number of currently available drugs for the treatment of diabetic complications, we have carried out a structure-based de novo design and synthesis in an attempt to identify new aldose reductase inhibitors. With the LEGEND program, we have designed 200 chemical structures that fit into the ligand binding site of the crystal structure of the enzyme. After their visual inspection and assessment of synthetic feasibility, four compounds were chosen to be synthesized. These compounds were all found to have reasonable inhibitory activities (IC50 = 17-91 microM), indicating the first successful generation of nonpeptide drug leads that have been obtained using a rational de novo design approach.

Peptide Chemistry 1992, 1993

Real-time outdoor navigation in highly dynamic environments is an crucial problem. The recent lit... more Real-time outdoor navigation in highly dynamic environments is an crucial problem. The recent literature on real-time static SLAM don't scale up to dynamic outdoor environments. Most of these methods assume moving objects as outliers or discard the information provided by them. We propose an algorithm to jointly infer the camera trajectory and the moving object trajectory simultaneously. In this paper, we perform a sparse scene flow based motion segmentation using a stereo camera. The segmented objects motion models are used for accurate localization of the camera trajectory as well as the moving objects. We exploit the relationship between moving objects for improving the accuracy of the poses. We formulate the poses as a factor graph incorporating all the constraints. We achieve exact incremental solution by solving a full nonlinear optimization problem in real time. The evaluation is performed on the challenging KITTI dataset with multiple moving cars.Our method outperforms the previous baselines in outdoor navigation.

Proteins: Structure, Function, and Genetics, 1993

We present calculations of the absolute and relative binding free energies of complexation of str... more We present calculations of the absolute and relative binding free energies of complexation of streptavidin with biotin and its analogs by means of a thermodynamic free energy perturbation method implemented with molecular dynamics. Using the recently solved crystal structure of the streptavidin-biotin complex, biotin was mutated into a dummy molecule as well as thiobiotin and iminobiotin both in the protein and in solution. The calculated absolute binding free energy was dependent on the simulation model used. Encouragingly, the "best models" provided a reasonable semiquantitative reproduction (-20 to-22 kcallmol)

Proceedings of the National Academy of Sciences, 1993

Free energy perturbation methods using molecular dynamics have been used to calculate the absolut... more Free energy perturbation methods using molecular dynamics have been used to calculate the absolute free energy of association of two ligand-protein complexes. The calculations reproduce the significantly more negative free energy of association of biotin to streptavidin, compared to N-L-acetyltryptophanamide/alpha-chymotrypsin. This difference in free energy of association is due to van der Waals/dispersion effects in the nearly ideally performed cavity that streptavidin presents to biotin, which involves four tryptophan residues.

Journal of Theoretical Biology, 1982

Recent studies (Ohtsuki, 1979, 1980) have shown that troponin T (tropomysin binding component of ... more Recent studies (Ohtsuki, 1979, 1980) have shown that troponin T (tropomysin binding component of troponin complex) is a rod-shaped molecule of approximately 9 nm in length and associated with filamentous tropomyosin. The region of residues 90 to 148 of troponin T, which has been confirmed as a main portion of helix-rich fragment which strongly binds to tropomyosin (Jackson, Amphlett & Perry, 1975, Pearlstone & Smillie, 1977), was predicted as a long stretch of a-helix by the method of secondary structure prediction (Nagano, 1977, Nagano et al., 1980). This paper deals with the mechanism of the specific binding explored by the extension of the method of schematic representation of helical interactions developed by McLachlan & Stewart (1976a) and, also, the method of scoring interactions of the staggered structures of collagen triplestranded coiled-coils developed by Hulmes et al. (1973). One of the most feasible structures of the specific binding complex was obtained as a triple-stranded coiled-coil made between a tropomyosin coiled-coil and the helical region of the specific binding fragment of troponin T, and confirmed by both LabQuip type and computer model building techniques. The techniques developed in the present work will be useful in elucidating the regulating mechanism of muscle contraction in its atomic details. The procedures and the steps for restricting the number of possible structures are outlined in Table 4.

Journal of the American Chemical Society, 2000

Journal of Synthetic Organic Chemistry, Japan, 1984

Journal of Medicinal Chemistry, 1987

alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic ... more alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic acids (monoester monoacids) and their dicarboxylic acids having the hydrophobic substituents at the 2- or 3-position of the thiazepinone ring were prepared and assayed for angiotensin-converting enzyme (ACE) inhibitory activity. The dicarboxylic acids having the pseudoequatorial amino groups at the 6-position and the pseudoequatorial hydrophobic substituents at the 2- or 3-position of the chair conformation of the thiazepinone ring had potent in vitro inhibitory activity. The monoester monoacids having the hydrophobic substituents at the 2-position suppressed pressor response to angiotensin I for a longer duration than those having the substituents at the 3-position when administered orally. The structure-activity relationship was studied by conformational energy calculations of the thiazepinone ring.