S Hirono

Publications (30)75.17 Total impact

• Source

  Available from: Hiroyuki Hirano

  Article: Quantitative structure-activity relationship (QSAR) analysis to predict drug-drug interactions of ABC transporter ABCG2.

  T Ishikawa, H Hirano, H Saito, K Sano, Y Ikegami, N Yamaotsu, S Hirono
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  ABSTRACT: Quantitative structure-activity relationship (QSAR) analysis is a practical approach by which chemical structure is quantitatively correlated with biological activity or chemical reactivity. Human ABC transporter ABCG2 exhibits broad substrate specificity toward structurally diverse compounds. To gain insight into the relationship between the molecular structures of compounds and the interaction with ABCG2, we have developed an algorithm that analyzes QSAR to evaluate ABCG2-drug interactions. In addition, to support QSAR analysis, we developed a high-speed screening method for analyzing the drug-drug interactions of ABCG2. Based on both experimental results and computational QSAR analysis data, we propose a hypothetical mechanism underlying ABC-mediated drug transport and its interaction with drugs.
  Mini Reviews in Medicinal Chemistry 06/2012; 12(6):505-14. · 2.53 Impact Factor
• Article: Molecular dynamics simulation of the calmodulin-trifluoperazine complex in aqueous solution.

  N Yamaotsu, M Suga, S Hirono
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  ABSTRACT: Trifluoperazine (TFP) has been widely studied in relation to its mode of binding and its inactivation of calmodulin (CaM). Most studies in solution have indicated that CaM has two high-affinity binding sites for TFP. The crystal structure of the 1:4 CaM-TFP complex (CaM-4TFP) shows that three TFP molecules bind to the C-domain of CaM, and that one TFP molecule binds to the N-domain. In contrast, the crystal structure of the 1:1 CaM-TFP complex (CaM-1TFP) shows that one TFP molecule binds to the C-domain. It has been thought that the binding of one TFP molecule to the C-domain is followed by binding to the N-domain. The crystal structure of the 1:2 CaM-TFP complex (CaM-2TFP), moreover, has recently been determined, showing that two TFP molecules bind to the C-domain. In order to determine the structure of the CaM-TFP complex and to clarify the interaction between CaM and TFP in solution, we performed a molecular dynamics simulation of the CaM-TFP complex in aqueous solution starting from the CaM-4TFP crystal structure. The obtained solution structure is very similar to the CaM-2TFP crystal structure. The computer simulation showed that the binding ability of the secondary binding site of the C-domain is higher than that of the primary binding site of the N-domain.
  Biopolymers 05/2001; 58(4):410-21. · 2.87 Impact Factor
• Article: Refinement of the NMR structures of alpha-conotoxin MI using molecular dynamics simulation with explicit solvent water and a full molecular force field.

  H Gouda, K Yamazaki, J Hasegawa, S Hirono
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  ABSTRACT: Three NMR structures of alpha-conotoxin MI, a potent antagonist of the nicotinic acetylcholine receptor, have been refined using molecular dynamics (MD) simulation with explicit water. Although the convergence of the NMR structures of alpha-conotoxin MI was not sufficient to provide detailed structural features, the average structures obtained from MD simulations converged to one conformation, providing structural characteristics. The resulting structure was also found to be consistent with the results of amide proton-exchange experiments. These results demonstrate that MD simulation with explicit solvent water is very useful in refining NMR structures.
  CHEMICAL & PHARMACEUTICAL BULLETIN 04/2001; 49(3):249-52. · 1.59 Impact Factor
• Article: Rational procedure for 3D-QSAR analysis using TRNOE experiments and computational methods: application to thermolysin inhibitors.

  A A Radwan, H Gouda, N Yamaotsu, H Torigoe, S Hirono
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  ABSTRACT: The success or failure of 3D QSAR, particularly CoMFA, is most strongly dependent, especially for flexible compounds, on the conformation of the molecule used in the analysis, and on the orientation of the molecule relative to the other molecules in 3D space (i.e., alignment). The present study suggests a rational procedure for the estimation of binding conformation that uses the transferred nuclear Overhauser effect (TRNOE) experiment in combination with conformational analysis using CAMDAS (Conformational Analyzer with Molecular Dynamics And Sampling) program that is developed in our laboratory. In the next step the TRNOE-obtained conformation can be used as a reference template in order to obtain alignment of other ligands, that have a common binding site. In this step we used the SUPERPOSE program created in our laboratory, in order to estimate the binding conformation of other compounds, and to simultaneously obtain the alignment of compounds for CoMFA. The resulting CoMFA models could be expected to closely reproduce the interaction mode with protein represented by the reported X-ray results. In order to confirm the validity of our procedure described above, we show its application in obtaining CoMFA models of thermolysin inhibitors. We obtained twenty CoMFA models, and that with the highest q2 value (q2 = 0.701) was found to provide an interaction mode very similar to that represented by the X-ray results.
  Drug Design and Discovery 02/2001; 17(3):265-81.
• Article: Three-dimensional structure-activity relationship analysis between motilin and motilide using conformational analysis and a novel molecular superposing method.

  H Gouda, T Sunazuka, S Omura, S Hirono
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  ABSTRACT: Motilide, an erythromycin derivative, has been shown to equal activity to that of motilin as an agonist at the motilin receptor. However, there is little information on the three-dimensional (3D) structure-activity relationship between these two molecules, largely because they have quite different structures. In this study, we applied a rational computational procedure consisting of conformational analysis and a novel superposing method to investigate the 3D structure-activity relationship between motilide and motilin. We propose common 3D structural features between these molecules, which may be important for their similar activity.
  CHEMICAL & PHARMACEUTICAL BULLETIN 12/2000; 48(11):1835-7. · 1.59 Impact Factor
• Article: Estimation of active conformations of drugs by a new molecular superposing procedure.

  K Iwase, S Hirono
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  ABSTRACT: We have developed a new program, SUPERPOSE, to superpose two molecules based on the physicochemical properties of functional atoms within individual molecules. SUPERPOSE treats a pseudo-molecule consisting of functional atoms instead of a real molecule. Four types of physicochemical properties--hydrophobicity, presence of a hydrogen-bonding donor, presence of a hydrogen-bonding acceptor and presence of a hydrogen-bonding donor/acceptor--were supposed and a score was given to each overlap. When functional atoms with the same physicochemical properties were overlapped, points were added to the score, and when the functional atoms with different physicochemical properties were overlapped, points were subtracted. We applied SUPERPOSE to 12 pairs of 24 enzyme inhibitors and found that the best scored overlay for each inhibitor pair could successfully reproduce the superposition obtained from X-ray crystallography. Next, we applied SUPERPOSE to estimate the active conformations of the thrombin inhibitors MQPA, 4-TAPAP and NAPAP. Superpositions of conformers sampled by the high-temperature molecular dynamics calculation with respect to the three inhibitors were performed, and 13 sets of conformers having the best common overlay to the three inhibitors were selected. One among 13 sets was consistent with the superposition of the active conformations derived from the X-ray crystallography of the thrombin-inhibitor complexes.
  Journal of Computer-Aided Molecular Design 10/1999; 13(5):499-512. · 3.39 Impact Factor
• Article: Analysis of affinities of penicillins for a class C beta-lactamase by molecular dynamics simulations.

  K Tsuchida, N Yamaotsu, S Hirono
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  ABSTRACT: We present a calculation for the binding free energy difference between two complexes of the class C beta-lactamase from Enterobacter cloacae with foramidocillin (FOPC) and with piperacillin (PIPC). The calculation was carried out by means of the thermodynamic integration (TI) method implemented with molecular dynamics (MD). By use of the available crystal structure of the class C beta-lactamase from E. cloacae, the structures of the beta-lactamase-FOPC (FOPC complex) and beta-lactamase-PIPC (PIPC complex) complexes were built by molecular modeling and equilibrated with MD simulations. FOPC were gradually converted into PIPC in both the solution and the enzyme system by means of MD/TI methods during the MD simulation. The structure of the PIPC complex as derived by the MD/TI simulation was similar to that of the PIPC complex obtained from molecular modeling. The calculated difference in the free energy of binding (deltadeltaGbind) was -2.2 kcal/mol. This compares well with the experimental value of -1.5 kcal/mol. The results indicate that the binding affinity of FOPC is lower than that of PIPC because of the greater difficulty of desolvation for FOPC upon binding to the enzyme. This calculation suggests that the desolvation of the ligand, as well as its interaction with the beta-lactamase, is important in understanding the relative affinity of the ligands with beta-lactamase.
  Drug Design and Discovery 09/1999; 16(2):145-53.
• Article: Solution structure of alpha-conotoxin ImI determined by two-dimensional NMR spectroscopy.

  H Gouda, S Hirono
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  ABSTRACT: The three-dimensional structure of alpha-conotoxin ImI, a potent antagonist targeting the neuronal alpha7 subtype of nicotinic acetylcholine receptor (nAChR), has been investigated by NMR spectroscopy. On the basis of 181 experimental constraints, a total of 25 converged structures were obtained. The average pairwise atomic root mean square difference is 0.40+/-0.11 A for the backbone atoms. The resulting structure indicates the presence of two successive type I beta-turns and a 310 helix for residues Cys2-Cys8 and Ala9-Arg11, respectively, and shows a significant structural similarity to that of alpha-conotoxin PnIA, which is also selective for the neuronal nAChR.
  Biochimica et Biophysica Acta 06/1999; 1431(2):384-94. · 4.66 Impact Factor
• Article: Determination of binding conformations of drugs to human serum albumin by transferred nuclear overhauser effect measurements and conformational analyses using high-temperature molecular dynamics calculations.

  Y Matsushita, H Gouda, H Tsujishita, S Hirono
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  ABSTRACT: The binding conformations of oxyphenbutazone (OXY), Nepsilon-dansyl-L-lysine (DNS-LYS), and furosemide (FU) to human serum albumin (HSA) have been investigated by molecular dynamics (MD) calculations and transferred nuclear Overhauser effect (TRNOE) measurements. We have combined distance information obtained from the Conformational Analyzer with Molecular Dynamics And Sampling (CAMDAS) calculation and experimental NOE spectroscopy measurements to determine a "binding conformation" for each drug which binds to site I of HSA. For OXY, only one conformer (conf9) among the conformer set generated by MD calculation satisfied the distance restraint conditions obtained from TRNOE measurements. For DNS-LYS and FU, 17 and 5 conformers satisfied distance restraint conditions, respectively. The structure of conf9 of OXY was taken as a "template" to choose binding conformers for DNS-LYS and FU. By fitting the "template" to the 17 conformers of DNS-LYS and 5 conformers of FU, we could efficiently obtain one binding conformer for DNS-LYS (conf144) and FU (conf26). It is suggested from the feature of the binding conformation that the three-dimensional location of a hydrophobic aromatic ring, alkyl chain, and electronegative functional group is important for binding to site I of HSA. This method, which combines MD calculations and NOE information, is thought to be effective for determining the binding conformation of drugs to HSA.
  Journal of Pharmaceutical Sciences 03/1998; 87(3):379-86. · 3.06 Impact Factor
• Article: Solution structure of alpha-conotoxin MI determined by 1H-NMR spectroscopy and molecular dynamics simulation with the explicit solvent water.

  H Gouda, K Yamazaki, J Hasegawa, Y Kobayashi, Y Nishiuchi, S Sakakibara, S Hirono
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  ABSTRACT: The conformation of alpha-conotoxin MI, a potent antagonist of the nicotinic acetylcholine receptor, has been investigated in aqueous solution. Two-dimensional NMR experiments and simulated annealing calculations provide the overall topology of alpha-conotoxin MI; then molecular dynamics simulation with the explicit solvent water was followed in order to obtain a more reliable solution structure. The resulting conformation indicates the presence of a 3(10) helix and a type I beta-turn for residues Pro6-Cys8 and Gly9-Try12, respectively, and shows a significant structural similarity to that of alpha-conotoxin GI, which has biological activity similar to that of MI. The present study provides a molecular basis for the alpha-conotoxin-receptor interaction.
  Biochimica et Biophysica Acta 01/1998; 1343(2):327-34. · 4.66 Impact Factor
• Article: CAMDAS: an automated conformational analysis system using molecular dynamics. Conformational Analyzer with Molecular Dynamics And Sampling.

  H Tsujishita, S Hirono
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  ABSTRACT: We present an automated conformational analysis program, CAMDAS (Conformational Analyzer with Molecular Dynamics And Sampling). CAMDAS performs molecular dynamics (MD) calculations for a target molecule and samples conformers from the trajectory of the MD. The program then evaluates the similarities between each of the sampled conformers in terms of the root-mean-square deviations of the atomic positions, clusters similar conformers, and finally prints out the clustered conformers. This MD-based conformational analysis is a broadly used method, and CAMDAS is intended to provide a convenient framework for the method. CAMDAS has the ability to find the representative conformers automatically from an arbitrarily given structure of the molecule. The accuracy of the program was examined using N-acetylalanine-N'-methylamide, and the obtained result was consistent with that of the systematic search method. In the test calculation of cyclodecane, CAMDAS could identify most of the known conformers and their conformational enantiomers by examining only 5000 conformers. In addition, the potential-scaled method, which we have developed previously as an accelerating technique for MD, could find two additional conformers of cyclodecane that have not been reported. CAMDAS presents a convenient way to find the energetically possible conformers of a molecule, which is needed especially in the early stage of drug design.
  Journal of Computer-Aided Molecular Design 06/1997; 11(3):305-15. · 3.39 Impact Factor
• Article: [Computer simulations using molecular dynamics methods].

  S Hirono, H Gouda, K Ebisawa
  Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 06/1997; 42(7 Suppl):1015-22.
• Source

  Available from: Hiroyuki Hirano

  Article: Prediction of the rodent carcinogenicity of organic compounds from their chemical structures using the FALS method.

  I Moriguchi, H Hirano, S Hirono
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  ABSTRACT: Fuzzy adaptive least-squares (FALS), a pattern recognition method recently developed in our laboratory for correlating structure with activity rating, was used to generate quantitative structure-activity relationship (QSAR) models on the carcinogenicity of organic compounds of several chemical classes. Using the predictive models obtained from the chemical class-based FALS QSAR approach, the rodent carcinogenicity or noncarcinogenicity of a group of organic chemicals currently being tested by the U.S. National Toxicology Program was estimated from their chemical structures.
  Environmental Health Perspectives 11/1996; 104 Suppl 5:1051-8. · 7.04 Impact Factor
• Source

  Available from: Fumiko Yoshii

  Article: Construction of a quantitative three-dimensional model for odor quality using comparative molecular field analysis (CoMFA).

  F Yoshii, S Hirono
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  ABSTRACT: A quantitative structure-activity relationship (QSAR) study of odorants was performed taking an odor as an activity. As an example, we took the 'green odor of pyrazine derivations' as an activity. Conformational analysis of the pyrazine derivatives was performed, and conformers were selected using the longest side-length of a circumscribed box (LLCB) as a criterion. Comparative molecular field analysis (CoMFA) was used to elucidate the three-dimensional (3D) structural features of the derivatives. As a result, it was found that the steric and electrostatic features of the derivations were correlated with human olfactory detection threshold values. We constructed a quantitative 3D model using the graphic views of CoMFA and partial structures of the derivatives. The prediction of human olfactory detection threshold values of other pyrazine derivatives with green odor was possible by using the 3D model. As another example, we took the 'sweet odor of compounds with various structures' as an activity. A quantitative 3D model for sweet odor was constructed in the same manner. Analysing the structural features of odorants by CoMFA and constructing 3D models for several important odor qualities would help to (i) explain or predict human olfactory detection threshold values of interesting odorants, (ii) design new odorants by suggesting the steric and electrostatic requirements, and (iii) elucidate the mechanism of odorant-receptor interaction.
  Chemical Senses 05/1996; 21(2):201-10. · 2.60 Impact Factor
• Source

  Available from: nih.gov

  Article: Modeling of the three-dimensional structure of polypeptides in solution using potential-scaled/hot-solute molecular dynamics.

  H Tsujishita, I Moriguchi, S Hirono
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  ABSTRACT: We present here an efficient and accurate procedure for modeling of the three-dimensional structures of polypeptides in the explicit solvent water based on molecular dynamics calculations. Using the toxic domain analog of heat-stable enterotoxin as a model peptide, we examined the utilities of two molecular dynamics techniques with the system containing the explicit solvent. One is the potential-scaled molecular dynamics that had been designed for effective conformational analyses of biomolecules with the explicit solvent water by partially scaling down the potential energies involved in the solute molecules. The other is the variation of Berendsen's weak coupling method (referred to as "hot-solute" method), in which only the solute of the system is heated to a high temperature while the solvent is kept at a normal temperature. Each method successfully increased the rate of folding of the peptides, and the most effective was a combination of the two methods. Moreover, the final structure obtained via cooling process successfully reproduced the experimentally known structure from the extended amino acid sequence using only the distance restraints representing three disulfide bonds in the peptide. Additional distance restraints derived from some of the NOE cross peaks accelerated the folding of the peptide, but gave almost the same structure as in the case without these additional restraints. Because a similar calculation without the explicit solvent could not reproduce the known structure, it is suggested that the explicit solvent water could play an important role in the modeling. The methods presented here have the potential for accurate modeling even when less experimental information was available.
  Biophysical Journal 07/1994; 66(6):1815-22. · 3.65 Impact Factor
• Article: Non-congeneric structure-pharmacokinetic property correlation studies using fuzzy adaptive least-squares: volume of distribution.

  S Hirono, I Nakagome, H Hirano, F Yoshii, I Moriguchi
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  ABSTRACT: The correlation of chemical structures with the volume of distribution of 373 miscellaneous medicinals was studied to construct an expert system for predicting the pharmacokinetic properties of organic chemicals. The compounds studied were classified into three groups; non-aromatics, aromatics, and heteroaromatics. Their total body volumes of distribution observed in human adults were allotted into three ratings, and the relationships with chemical structure were analyzed using the fuzzy adaptive least-squares method recently developed in our laboratory. Quantitative relationship models formulated for the three structure groups gave significant information about factors influencing the volume of distribution, and were statistically reliable both in recognition and leave-one-out prediction despite the diversity and complexity of the structures of the compounds investigated.
  Biological & Pharmaceutical Bulletin 06/1994; 17(5):686-90. · 1.66 Impact Factor
• Article: Structure-activity relationship study of 6-O-methylerythromycin 9-O-substituted oxime derivatives.

  Y Kawashima, Y Yamada, T Asaka, Y Misawa, M Kashimura, S Morimoto, T Ono, T Nagate, K Hatayama, S Hirono
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  ABSTRACT: In order to develop new-generation macrolide antibiotics active against erythromycin (EM)-resistant strains, a series of 6-O-methyl EM 9-O-substituted oxime derivatives was synthesized and evaluated for antibacterial activity against EM-resistant (S. aureus J-109) and susceptible (S. aureus 209P) strains. To understand how substituents affect the biological activity, the quantitative structure-activity relationships (QSAR) was analyzed using the Hansch-Fujita method. With the EM-resistant strain, the positive coefficient for log P may indicate that higher hydrophobicity of molecules is favorable for antibacterial activity. The negative coefficients of the Sterimol parameters L, B1, and B5 may indicate that long, bulky substituents are unfavorable. With the EM-susceptible strain, the negative coefficient for log P may indicate that hydrophilicity is important for antibacterial activity. A short substituent is also required to improve the activity. Based on the QSAR model, a derivative (87) having an anthracenylmethyl moiety was synthesized to reinforce and confirm the correlation. The activity of 87 against the EM-resistant strain was significant. In QSARs of 6-O-methyl EM-A 9-O-substituted oxime derivatives, the difference of the contribution of log P to the antibacterial activity between EM-resistant and susceptible strains was clearly recognized.
  CHEMICAL & PHARMACEUTICAL BULLETIN 06/1994; 42(5):1088-95. · 1.59 Impact Factor
• Article: Non-congeneric structure-pharmacokinetic property correlation studies using fuzzy adaptive least-squares: oral bioavailability.

  S Hirono, I Nakagome, H Hirano, Y Matsushita, F Yoshii, I Moriguchi
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  ABSTRACT: Quantitative relationship between chemical structure and oral bioavailability of 188 non-congeneric organic medicinals were studied to construct an expert system for predicting pharmacokinetic properties of organic chemicals. The compounds studied were classified into three groups: non-aromatics, aromatics, and heteroaromatics. Their oral bioavailability data observed in human adults were allotted into three ratings, and the relationships with chemical structure were analyzed using fuzzy adaptive least-squares. Quantitative relationship models formulated for the three structure groups gave significant information about factors influencing bioavailability, and were statistically reliable in both recognition and leave-one-out prediction despite the diversity and complexity of the structures of the compounds investigated.
  Biological & Pharmaceutical Bulletin 03/1994; 17(2):306-9. · 1.66 Impact Factor
• Article: Solution structure of HIV-1 protease-allophenylnorstatine derivative inhibitor complex obtained from molecular dynamics simulation.

  R Kato, O Takahashi, Y Kiso, I Moriguchi, S Hirono
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  ABSTRACT: Structures of two enzyme-inhibitor complexes of human immunodeficiency virus-1 protease with allophenylnorstatine derivatives were obtained from molecular dynamics simulation in aqueous solution. The stronger inhibitor gave considerably smaller fluctuation at P3 site, which formed hydrogen bonding with the enzyme flap region.
  CHEMICAL & PHARMACEUTICAL BULLETIN 02/1994; 42(1):176-8. · 1.59 Impact Factor
• Article: Estimation of stabilities of staphylococcal nuclease mutants (Met32-->Ala and Met32-->Leu) using molecular dynamics/free energy perturbation.

  N Yamaotsu, I Moriguchi, S Hirono
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  ABSTRACT: We performed molecular dynamics (MD)/free energy perturbation (FEP) calculations to reproduce the experimental free energy difference of denaturation for staphylococcal nuclease mutant Met32-->Ala (M32A) and to predict the stability of the mutant Met32-->Leu (M32L). The calculated free energy difference of denaturation for the M32A of -1.9 kcal/mol was in good agreement with the experimental value. In the M32A, a small hydrophobic core formed by three aromatic rings (Tyr-27, Phe-34, Phe-76) in a wild-type crumbled as a result of exposure to water. The van der Waals interactions in the native state of the M32A were weaker than those of the wild-type, which strongly suggests that the Met-32 is important for the stability of the enzyme. The M32L has not been available yet, but is expected to retain the small hydrophobic core. The free energy difference of denaturation for the M32L was calculated to be 1.6 kcal/mol. The MD/FEP simulation showed that the native state structure of the M32L was only slightly changed when compared with that of the wild-type. It was suggested that the M32L is more stable than the wild-type because the electrostatic interactions in the denatured state are more disadvantageous than those in the native state.
  Biochimica et Biophysica Acta 01/1994; 1203(2):243-50. · 4.66 Impact Factor