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Noriaki Hirayama

Publications and source records attributed to Noriaki Hirayama.

12 recordsLinked to original sources
PubMed2007

[Docking method for drug discovery].

The effective integration of detailed structural information with computational chemistry, medicinal chemistry, and informatics transforms the dream of virtual screening into reality. One of the most important technologies essential for virtual screening is an effective docking method to find molecules that efficaciously interact with their target molecules. Since an efficient docking method can be a powerful tool for virtual screening, many different approaches to solving docking problems have been proposed. Docking problems have not yet been solved and none of the currently available programs are perfect in predicting all possible scenarios. Despite the limits and imperfections of the methodology, currently available docking methods are very useful for drug discovery. The basic principles and limits of docking methods together with matters for attention in applying the methods are described in this paper.

Binding Sites↗
PubMed2006

G-CSF receptor-binding cyclic peptides designed with artificial amino-acid linkers.

Designing small molecules that mimic the receptor-binding local surface structure of large proteins such as cytokines or growth factors is fascinating and challenging. In this study, we designed cyclic peptides that reproduce the receptor-binding loop structures of G-CSF. We found it is important to select a suitable linker to join two or more discontinuous sequences and both termini of the peptide corresponding to the receptor-binding loop. Structural simulations based on the crystallographic structure of KW-2228, a stable and potent analog of human G-CSF, led us to choose 4-aminobenzoic acid (Abz) as a part of the linker. A combination of 4-Abz with beta-alanine or glycine, and disulfide bridges between cysteins or homocysteins, gave a structure suitable for receptor binding. In this structure, the side-chains of several amino acids important for the interactions with the receptor are protruding from one side of the peptide ring. This artificial peptide showed G-CSF antagonistic activity in a cell proliferation assay.

4-Aminobenzoic Acid↗
PubMed2006

Construction of an additional metal-binding site in human metallothionein-2.

We have constructed a new metal-binding site in the human metallothionein-2 (hMT-2), using the protein as a scaffold to investigate the structure and function of metal-binding. Potential metal-binding sites were designed within hMT-2 on the basis of structures generated by homology modeling. Amino acid residues D11, C13, C26 and S28 in the beta-domain of hMT-2 (hMT-2beta) were found, by computer search, to form a potential tetrahedral Cys4 metal-binding site. Six mutant proteins were constructed with the following amino acid substitutions: D11C, S28C and D11C/S28C in hMT-2 and the same mutations in hMT-2beta, respectively. These single-mutant and double-mutant proteins bound one gram atom of cadmium or zinc ions per gram molecule of protein more than the corresponding wild-type proteins. The circular dichroism spectra suggested that the structures of the single-mutant proteins that bound Cd or Zn were similar to that of the D11C/S28C double-mutant proteins. To evaluate the metal-binding affinity of the mutant proteins, we performed pH titrations of wild-type and mutant proteins. The stability with changes in pH of all the mutant proteins was higher than that of the wild-type proteins, and that of the double-mutant D11C/S28C protein was highest. Consequently, it appears that we were able to create novel proteins that bound metal ions at high density and with high affinity.

Amino Acid Sequence↗
PubMed2005

Prediction of solvents suitable for crystallization of small organic molecules.

Selection of suitable solvent is essential for crystallization of pharmaceuticals. Based on chemical structures of 6397 compounds and 15 single solvents that were used to obtain their single crystals, correlations between the molecular characteristics and the solvents have been investigated by cheminformatics methods. Decision-tree and Bayesian-probability methods have been applied to make classification models. These two models are complementary in character in the present case. It has been proven that the prediction of the solvent rankings for particular compounds by use of the classification models is satisfactory from the practical point of view. The present study has demonstrated that cheminformatics methods could greatly help rational crystallization of small organic molecules such as pharmaceuticals.

Chemistry, Pharmaceutical↗
PubMed2005

Prediction of solubility of drugs by conductor-like screening model for real solvents.

The solubility of drugs in solvents is fundamentally important for drug development and manufacturing. As the experimental measurements of the solubility are extremely laborious tasks, reliable prediction methods are highly required. We have employed the conductor-like screening model for real solvents (COSMO-RS) in predicting the solubility of drugs and drug-like compounds in various solvent systems. We also evaluated the salt effect on the solubility of caffeine using this method. The present results demonstrated that COSMO-RS has reasonably reproduced the experimental data and have proved that this method is generally available in predicting the solubility of drugs.

Caffeine↗
PubMed2004

Ph4Dock: pharmacophore-based protein-ligand docking.

The development and validation of the program Ph4Dock is presented. Ph4Dock is a novel automated ligand docking program that makes best use of pharmacophoric features both in a ligand and at concave portions of a protein. By mapping of pharmacophores of the ligand to the pharmacophoric features that represent the concaves of the target protein, Ph4Dock realizes an efficient and accurate prediction of the binding modes between the ligand and the protein. To validate the potential of this unique docking algorithm, we have selected 43 reliable crystal structures of protein-ligand complexes. All of the ligands are druglike, and they are varied in nature. The diffraction-component precision index (DPI) originally used in crystallography was applied in this study in order to evaluate the docking results quantitatively. The root-mean-square deviation (rmsd) between non-hydrogen atoms of the ligand in the prediction and experimental results were analyzed using DPI. The rmsd values for 25 structures, consisting of almost 60% of the dataset, are less than three times of the corresponding DPI values. It means that the precision of docking results obtained by Ph4Dock is mostly equivalent to the experimental error in these cases. The present study has demonstrated that Ph4Dock can accurately reproduce the experimentally determined docking modes if the reliable crystal structures are used. Normally the success rate of the docking is judged using rmsd < or = 2.0 A as the criterion. The Ph4Dock marked an appreciably good success rate of 86% based on this criterion.

Binding Sites↗
PubMed2004

Molecular mechanism of dielectrically controlled optical resolution (DCR).

We have recently found the first example of dielectrically controlled optical resolution (DCR). By adjusting the dielectric constant of the solvent used in the resolution process, each optical isomer of (R,S)-alpha-amino-epsilon-caprolactam can be selectively obtained using N-tosyl-(S)-phenylalanine as a chiral selector. The molecular mechanism of DCR has been investigated by comparing the molecular and crystal structures of the optical selector, its target substrate and their diastereomeric salts. Strong hydrophobic interactions between the phenyl rings of the optical selector govern the molecular aggregation of the selectors and form a hydrophilic layer in which molecular recognition takes place. The recognition site in the hydrophilic layer can inherently identify both of the isomers. The dielectric constant of the solvent used in the discrimination process controls the intermolecular interaction which determines the isomer to be selected. The molecular mechanism of DCR disclosed in this study strongly suggests that DCR is not a specific but a general phenomenon. This method can be applicable to a large variety of optical resolution processes.

Caprolactam↗
PubMed2002

Interactions of arsenic with human metallothionein-2.

Arsenic is a toxic element that is found in the atmosphere, as well as in aquatic and terrestrial environments. We have demonstrated that As(3+) binds to human metallothionein-2 (hMT-2) by UV absorption spectroscopy, inductively coupled plasma-atomic emission spectrometry (ICP-AES), and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). MALDI-TOF-MS revealed that the structure of the adduct formed by arsenic and hMT-2 (As-hMT-2) was not homogeneous. The maximum molar ratio of arsenic to hMT-2 was found to be more than 6:1 on ICP-AES, UV absorption spectroscopy and MALDI-TOF-MS. The ratio of the number of sulfhydryl groups in hMT-2 that bound arsenic was 3:1, which is the same as the ratios reported previously for arsenic-glutathione and arsenic-phytochelatin complexes.

Animals↗
PubMed2002

Alteration of substrate specificity of cholesterol oxidase from Streptomyces sp. by site-directed mutagenesis.

Despite the structural similarities between cholesterol oxidase from Streptomyces and that from Brevibacterium, both enzymes exhibit different characteristics, such as catalytic activity, optimum pH and temperature. In attempts to define the molecular basis of differences in catalytic activity or stability, substitutions at six amino acid residues were introduced into cholesterol oxidase using site-directed mutagenesis of its gene. The amino acid substitutions chosen were based on structural comparisons of cholesterol oxidases from Streptomyces and BREVIBACTERIUM: Seven mutant enzymes were constructed with the following amino acid substitutions: L117P, L119A, L119F, V145Q, Q286R, P357N and S379T. All the mutant enzymes exhibited activity with the exception of that with the L117P mutation. The resulting V145Q mutant enzyme has low activities for all substrates examined and the S379T mutant enzyme showed markedly altered substrate specificity compared with the wild-type enzyme. To evaluate the role of V145 and S379 residues in the reaction, mutants with two additional substitutions in V145 and four in S379 were constructed. The mutant enzymes created by the replacement of V145 by Asp and Glu had much lower catalytic efficiency for cholesterol and pregnenolone as substrates than the wild-type enzyme. From previous studies and this study, the V145 residue seems to be important for the stability and substrate binding of the cholesterol oxidase. In contrast, the catalytic efficiencies (k(cat)/K(m)) of the S379T mutant enzyme for cholesterol and pregnenolone were 1.8- and 6.0-fold higher, respectively, than those of the wild-type enzyme. The enhanced catalytic efficiency of the S379T mutant enzyme for pregnenolone was due to a slightly high k(cat) value and a low K(m) value. These findings will provide several ideas for the design of more powerful enzymes that can be applied to clinical determination of serum cholesterol levels and as sterol probes.

Amino Acid Sequence↗