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Biomedical subjects

I Moriguchi

Publications and source records attributed to I Moriguchi.

At least 19 recordsLinked to original sources
PubMed1996

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

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.

Animals↗
PubMed1994

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

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.

Amino Acid Sequence↗
PubMed1994

Non-congeneric structure-pharmacokinetic property correlation studies using fuzzy adaptive least-squares: oral bioavailability.

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.

Administration, Oral↗
PubMed1994

Non-congeneric structure-pharmacokinetic property correlation studies using fuzzy adaptive least-squares: volume of distribution.

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 Availability↗
PubMed1994

Binding of carprofen to human and bovine serum albumins.

The binding of carprofen (CP) to human serum albumin (HSA) and bovine serum albumin (BSA) was compared using equilibrium dialysis method. The affinity of CP for the primary binding site was BSA > HSA. However, the number of primary binding sites (n1) was 1.94 on HSA, considerably greater than that on BSA (0.79). The displacement of the binding of CP to HSA and BSA was studied in the presence of phenylbutazone (PB, site I marker), ibuprofen (IB, site II marker) or 2,3,5-triiodobenzoic acid (TIB, both site I and II marker). The binding of CP to HSA was altered by PB, IB and TIB, while the binding of CP to BSA was not changed by PB, although it was reduced by IB and TIB. These results suggested that, for the binding of CP, HSA has two major sites (site I and site II), whereas BSA has a single primary site (site II). The binding characteristics of 2-anthracenecarboxylic acid with HSA and BSA were found quite similar to those of CP. Thus, it seemed that long, planar compounds with a carboxyl group at one end can bind to site I and site II on HSA, but only to site II on BSA. The difference between HSA and BSA in the affinity of site I may be due to the difference in the basic and hydrophobic amino acid residues.

Animals↗
PubMed1994

[Development of quantitative structure-activity relationships and computer-aided drug design].

Recent development of quantitative structure-activity relationships (QSARs) and computer-aided drug design contributed by the author and his coworkers was briefly reviewed. Fuzzy adaptive least-squares (FALS), a pattern recognition method for analysing structure-activity rating data to generate QSAR models was developed. A novel feature of FALS is that the degree to which each sample belongs to its activity class is given by a fuzzy membership function. Using FALS, non-congeneric QSAR analyses of carcinogenicity, mutagenicity, and six kinds of pharmacokinetic properties of miscellaneous organic chemicals were performed to construct predictive models for drug design. In these QSAR analyses, the values of log P (partition coefficient in octanol/water) calculated by the simple method of Moriguchi et al. were used as the descriptor for hydrophobicity. The method of Moriguchi et al. is not only simple and convenient but also reliable in the application to 22 drugs selected by Rekker et al. compared to the Rekker method and the Hansch-Leo method. Lastly, a heulistic search method for active conformers using molecular mechanical conformational analysis and principal component analysis was proposed.

Animals↗
PubMed1993

Estimation of stabilities of staphylococcal nuclease mutants (Met32-->Ala and Met32-->Leu) using molecular dynamics/free energy perturbation.

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.

Enzyme Stability↗
PubMed1993

Molecular dynamics study of the stability of staphylococcal nuclease mutants: component analysis of the free energy difference of denaturation.

The stability of two mutants G88V (Gly-88-->Val) and A69T (Ala-69-->Thr) of staphylococcal nuclease was analyzed by molecular dynamics simulations. The calculated free energy differences of denaturation for G88V and A69T were -1.1 and -2.8 kcal/mol, respectively. These values are in good agreement with the experimental values. The free energy differences divided into electrostatic and van der Waals components were analyzed. These two mutants are mainly destabilized due to van der Waals interactions. There is little difference between the electrostatic contribution to the free energy change in the native state and that in the denatured state. In each mutant structure, a small cavity appears in the vicinity of the perturbed residue. It is suggested that intramolecular van der Waals interactions of the mutants are weaker than those of the wild-type. Furthermore, analyses of the contributions of each residue near the perturbed residue and of water to the free energy difference of denaturation suggest that the interaction between water and the perturbed residue plays a very important role in the stability of staphylococcal nuclease, and that a small hydrophobic core consisting of the three aromatic rings (Tyr-27, Phe-34, Phe-76) and the side chain of Met-32 is also important for the stability.

Alanine↗
PubMed1993

Structure-activity study of antihypertensive 1,4-dihydropyridine derivatives having nitrooxyalkyl moieties at the 3 and 5 positions.

1,4-Dihydropyridine derivatives having two nitrooxyalkyl moieties as esters at the 3 and 5 positions possess antihypertensive activity. To understand how substituents affect the biological activity, the quantitative structure-activity relationship (QSAR) of 27 compounds was analyzed using the Fuzzy adaptive least-squares (FALS 91) method. The QSAR models suggested that the hydrophobicity and electronic effect at the 4 position of the 1,4-dihydropyridine along with the special structures of the nitrooxyalkylester components are important for antihypertensive activity.

Animals↗
PubMed1992

Structure-activity studies of 3-benzoylpropionic acid derivatives suppressing adjuvant arthritis.

3-Benzoylpropionic acid derivatives possess an immunomodulative activity and suppress adjuvant arthritis. To understand how substituents affect the biological activity, the quantitative structure-activity relationships of 30 compounds were analyzed by the adaptive least-squares method. For the suppressing activity in rats, the electronic effects and the structural feature of the substituent on benzene ring were suggested to be important. To reinforce and confirm the correlation, 4 additional compounds of phenoxybutyric acid derivatives were synthesized and tested with the rat adjuvant-induced arthritis. These compounds were found to have potent suppressing activity.

Animals↗
PubMed1990

Quantitative structure-activity relationships for calmodulin inhibitors.

Using the discriminant analysis method, we completely distinguished 24 calmodulin inhibitors in three groups, as classified by Zimmer et al. The resultant discriminant functions distinguished the three groups in terms of positive potential surface area on the side chain, as well as the total and neutral surface areas on the ring in the inhibitor molecules. Group assignment of additional calmodulin inhibitors from other sources was then estimated according to the discriminant functions. The relationship between structure and inhibitory potency on calmodulin-activated phosphodiesterase for group I inhibitors, together with those estimated, was studied using the adaptive least squares method with several parameters dependent on molecular conformations. A "best conformer" was selected for each inhibitor on the basis of quantitative structure-activity relationship (QSAR). The results of QSAR analysis of group I inhibitors showed that hydrophobicity was important for the ring moiety but not for the side chain. The negative potential surface area of the side chain is necessary for activity. It is desirable for the nitrogen atom in the side chain, which is considered the center of the negative potential area, to be located far from the ring moiety. Thus, the ring moiety and side chain may possibly play different roles in interactions with the receptor system.

Calmodulin↗
PubMed1990

Fuzzy adaptive least squares and its use in quantitative structure-activity relationships.

Fuzzy adaptive least squares (FALS), a pattern recognition method designed to correlate molecular structure with activity rating, has been developed. A novel feature of FALS is that the degree to which each sample belongs to an activity class is given using a membership function. The algorithm involves an iterative modification of forcing factors to maximize the sum of the membership function values over all samples. This paper first describes the method and calculation procedure of FALS89 (1989 version of FALS), and then shows its application to the correlation of structure with a potency rating of anticarcinogenic mitomycin derivatives and arginine-vasopressin antagonists. FALS89 applied to these samples showed considerably high reliability in both recognition and leave-one-out prediction.

Antibiotics, Antineoplastic↗
PubMed1990

Inhibitory activity and protein binding of L-lysine derivatives as angiotensin converting enzyme inhibitors.

Four compounds 1a-4a containing one L-lysine residue in the molecule including a diastereomer mixture of lisinopril (N-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline) and N epsilon-carbobenzoxy-L-lysine derivatives 1b-4b of each of the four compounds were synthesized to compare the angiotensin converting enzyme (ACE) inhibitory activities in vitro and in vivo. They all showed high ACE inhibitory activity in vitro (IC50 = 0.14-42 nmol/l). A marked difference, however, was observed in inhibition of the pressor response to angiotensin I between 1a-4a (high activity) and 1b-4b (low activity). The binding of these compounds to human serum proteins in vitro was investigated by means of equilibrium dialysis and ultracentrifugation. Compounds 1b-4b showed higher levels of binding to serum albumin than that of the corresponding compounds 1a-4a, and the percentage of binding ranged from 20.1 to 89.1%. Furthermore, the inhibitory activity of compounds 1b-4b in vitro was decreased by the addition of albumin in a concentration-dependent manner. These results suggested that the difference in the protein binding rate of compounds is one of the important factors influencing the inhibitory activity in vivo.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Binding of pyrene-1-butyric acid to serum albumin: species differences.

Changes of the fluorescence spectra and quantum yield of pyrene-1-butyric acid (PYB) induced by rat (RSA), horse (HoSA), and pig serum albumins (PSA) and rat serum were compared at pH 7.4. RSA and rat serum caused marked quenching of the PYB fluorescence. On the contrary, HoSA and PSA increased the fluorescence intensity. In RSA and rat serum solutions, the PYB fluorescence intensity due to monomer emission was greatly diminished, and an additional emission due to excimer formation appeared at 480 nm. On the other hand, in the case of HoSA and PSA solutions, monomer emission gave rise to high fluorescence intensity and no excimer formation was observed. The binding parameters of PYB to RSA, HoSA, and PSA as well as human (HSA), bovine (BSA), rabbit (RbSA) and dog serum albumins (DSA) were compared by equilibrium dialysis method. The primary binding site affinity was in the order RSA greater than HSA greater than HoSA greater than RbSA greater than DSA greater than or equal to BSA greater than PSA. However, for RSA and HSA, which showed reduced monomer emission and clear excimer fluorescence, the primary binding site number (n1) was 2.71 and 2.90, respectively, considerably greater than those values for the other serum albumins. These findings suggest that PYB binds to RSA and HSA as a dimer. On the other hand, PYB appears to bind with BSA, RbSA, DSA and HoSA as a monomer. The primary binding site was not clearly recognized in PSA, which showed little enhancement of fluorescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Synthesis and quantitative structure-activity relationship analysis of N-triiodoallyl- and N-iodopropargylazoles. New antifungal agents.

New series of N-(2,3,3-triiodoallyl) and N-(3-iodopropargyl) azole derivatives (100 compounds) involving pyrrole, pyrazole, imidazole, triazole, and tetrazole nuclei were synthesized successively with the aid of quantitative structure-activity relationship (QSAR) analysis to obtain potent antifungal agents. Starting from the derivatives of nitropyrrole-containing antibiotics, the QSAR analysis of the pyrrole derivatives against Candida albicans and Trichophyton mentagrophytes strains indicated the positive contribution of the nitro group and negative effect of the size of molecule. Further application of the QSAR analysis on the multi-azole derivatives revealed the importance of hydrophobicity and electronegativity as well as steric effect to the activities and led to the synthesis of one of the most potent iodo compounds, 2-(2,3,3-triiodoallyl)tetrazole (67, ME1401).

Allyl Compounds↗