Quantum pharmacological studies on antimalarial drugs

Summary Linear models for the relation between electronic structure and antimalarial activity of chloroquine drugs have been investigated, based on CNDO/2 molecular orbital calculations. The results indicate that changes in electron density on the atoms N1, N2, C4, C9, and C10 have the strongest influence on the pharmacological activity, so that these atoms can be assumed to form the main active center of these drugs. Correlations improve, if substitution on the nucleus of chloroquine and side chain variations are treated separately. The models found seem to be a useful tool for designing new drugs within the chloroquine series.

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Quantenchemisch-pharmakologische Untersuchungen von Antimalaria-Wirkstoffen

Zusammenfassung Auf der Basis von CNDO/2-Rechnungen wurden lineare Modelle für die Relation zwischen Elektronenverteilung und der Antimalaria-Aktivität von Chlorochinen untersucht. Es zeigte sich, daß Veränderungen in den Elektronendichten der Atome N1, N2, C4, C9 und C10 den stärksten Einfluß auf die pharmakologische Wirkung haben. Es kann somit angenommen werden, daß diese Atome die hauptsächlich aktiven Zentren der Verbindung sind. Die Korrelation wird verbessert, wenn die Substitution am Chlorochin-Kern und Variationen der Seitenketten separat behandelt werden. Die aufgefundenen Modellvorstellungen sollten ein nützliches Werkzeug zur gezielten Synthese neuer Wirkstoffe innerhalb der Chlorochin-Reihe darstellen.

     

Cellulase-Producing Bacteria from Thai Higher Termites, <Emphasis Type="Italic">Microcerotermes</Emphasis> sp.: Enzymatic Activities and Ionic Liquid Tolerance

The three highest hydrolysis-capacity-value isolates of Bacillus subtilis (A 002, M 015, and F 018) obtained from Thai higher termites, Microcerotermes sp., under different isolation conditions (aerobic, anaerobic, and anaerobic/aerobic) were tested for cellulase activities—FPase, endoglucanase, and β-glucosidase—at 37 °C and pH 7.2 for 24 h. Their tolerance to an ionic liquid, 1-butyl-3-methylimidazolium chloride ([BMIM]Cl), was also investigated. The results showed that the isolate M 015 provided the highest endoglucanase activity whereas the highest FPase and β-glucosidase activities were observed for the isolate F 018. The isolate F 018 also showed the highest tolerance to [BMIM]Cl in the range of 0.1–1.0 vol.%. In contrast, the isolate A 002 exhibited growth retardation in the presence of 0.5–1.0 vol.% [BMIM]Cl.     

A sequential enantioselective, organocatalytic route to chiral 1,2-oxazines and chiral pyridazines

A sequential, organocatalysed asymmetric reaction to access chiral 1,2-oxazines and chiral pyridazines is reported, which proceeds in moderate to good yields and good to excellent enantioselectivities.     

Structural basis for the temperature-induced transition of D-amino acid oxidase from pig kidney revealed by molecular dynamic simulation and photo-induced electron transfer

The structural basis for the temperature-induced transition in the D-amino acid oxidase (DAAO) monomer from pig kidney was studied by means of molecular dynamic simulations (MDS). The center to center (Rc) distances between the isoalloxazine ring (Iso) and all aromatic amino acids (Trp and Tyr) were calculated at 10 °C and 30 °C. Rc was shortest in Tyr224 (0.82 and 0.88 nm at 10 and 30 °C, respectively), and then in Tyr228. Hydrogen bonding (H-bond) formed between the Iso N1 and Gly315 N (peptide), between the Iso N3H and Leu51 O (peptide) and between the Iso N5 and Ala49 N (peptide) at 10 °C, whilst no H-bond was formed at the Iso N1 and Iso N3H at 30 °C. The H-bond of Iso O4 with Leu51 N (peptide) at 10 °C switched to that with Ala49 N (peptide) at 30 °C. The reported fluorescence lifetimes (228 and 182 ps at 10 and 30 °C, respectively) of DAAO were analyzed with Kakitani and Mataga (KM) ET theory. The calculated fluorescence lifetimes displayed an excellent agreement with the observed lifetimes. The ET rate was fastest from Tyr224 to the excited Iso (Iso*) at 10 °C and from Tyr314 at 30 °C, despite the fact that the Rc was shortest between Iso and Tyr224 at both temperatures. This was explained by the electrostatic energy in the protein. The differences in the observed fluorescence lifetimes at 10 and 30 °C were ascribed to the differences in electron affinity of the Iso* at both temperatures, in which the free energies of the electron affinity of Iso* at 10 and 30 °C were -8.69 eV and -8.51 eV respectively. The other physical quantities related to ET did not differ appreciably at both temperatures. The electron affinities at both temperatures were calculated with a semi-empirical molecular orbital method (MO) of PM6. Mean calculated electron affinities over 100 snapshots with 0.1 ps intervals were -7.69 eV at 10 °C and -7.59 eV at 30 °C. The difference in the calculated electron affinities, -0.11 eV, was close to the observed difference in the free energies, -0.18 eV. The present quantitative analysis predicts that the highest ET rate can occur from a donor with longer donor-acceptor distance, which was explained by differences in electrostatic energy.     

Comparative molecular field analysis of artemisinin derivatives: Ab initio versus semiempirical optimized structures

Based on the belief that structural optimization methods, producing structures more closely to the experimental ones, should give better, i.e. more relevant, steric fields and hence more predictive CoMFA models, comparative molecular field analyses of artemisinin derivatives were performed based on semiempirical AM1 and HF/3-21G optimized geometries. Using these optimized geometries, the CoMFA results derived from the HF/3-21G method are found to be usually but not drastically better than those from AM1. Additional calculations were performed to investigate the electrostatic field difference using the Gasteiger and Marsili charges, the electrostatic potential fit charges at the AM1 level, and the natural population analysis charges at the HF/3-21G level of theory. For the HF/3-21G optimized structures no difference in predictability was observed, whereas for AM1 optimized structures such differences were found. Interestingly, if ionic compounds are omitted, differences between the various HF/3-21G optimized structure models using these electrostatic fields were found.     

Display of Organophosphorus Hydrolase on the Cyanobacterial Cell Surface Using <Emphasis Type="Italic">Synechococcus</Emphasis> Outer Membrane Protein A as an Anchoring Motif

The display of proteins to cyanobacterial cell surface is made complex by combination of Gram-positive and Gram-negative features of cyanobacterial cell wall. Here, we showed that Synechococcus outer membrane protein A (SomA) can be used as an anchoring motif for the display of organophosphorus hydrolase (OPH) on cyanobacterial cell surface. The OPH, capable of degrading a wide range of organophosphate pesticides, was fused in frame to the carboxyl-terminus of different cell-surface exposed loops of SomA. Proteinase K accessibility assay and immunostaining visualized under confocal laser scanning microscopy demonstrated that a minor fraction of OPH with 12 histidines fused in frame with the third cell-surface exposed loop of SomA (SomAL3-OPH12H) was displayed onto the outermost cell surface with a substantial fraction buried in the cell wall, whereas OPH fused in frame with the fifth cell-surface exposed loop of SomA (SomAL5-OPH) was successfully translocated across the membrane and completely displayed onto the outermost surface of Synechococcus. The successful display of the functional heterologous protein on cell surface provides a useful model for variety of applications in cyanobacteria including screening of polypeptide libraries and whole-cell biocatalysts by immobilizing enzymes.     

Simultaneous analyses of photoinduced electron transfer in the wild type and four single substitution isomers of the FMN binding protein from Desulfovibrio vulgaris, Miyazaki F

The mechanism of photoinduced electron transfer (PET) from the aromatic amino acids (Trp32, Tyr35 and Trp106) to the excited flavin mononucleotide (FMN) in the wild type (WT) and four single amino acid substitution isomers (E13T, E13Q, W32A and W32Y) of FMN binding protein (FBP) from the Desulfovibrio vulgaris (Miyazaki F) were simultaneously analyzed (Method A) with the Marcus-Hush (MH) theory and Kakitani-Mataga (KM) theory using ultrafast fluorescence dynamics of these proteins. In addition, the PET mechanism of the WT, E13T and E13Q FBP systems (Method B) were also analyzed with both MH and KM theories. The KM theory could describe all of the experimental fluorescence decays better than the MH theory by both Methods A and B. The PET rates were found to largely depend on the electrostatic energies between photo-products, isoalloxazine (Iso) anion and the PET donor cations, and the other ionic groups, and hence on static dielectric constants. The dielectric constant (ε(0)(DA)) around the PET donors and acceptor was separately determined from those (ε(0)(j), j = WT, E13T, E13Q, W32Y and W32A) in the domain between the Iso anion or the donor cations and the other ionic groups in the proteins. The values of ε(0)(DA) were always lower than those of ε(0)(j), which is reasonable because no amino acid exists between the PET donors and acceptor in all systems. The values of the dielectric constants ε(0)(j) (j = WT, E13T and E13Q) were similar to those obtained previously from the analysis of the crystal structures and the average lifetimes of these FBP proteins. Energy gap law in the FBP systems was examined. An excellent parabolic function of the logarithms of the PET rates was obtained against the total free energy gap. The PET in these FBP isomers mostly took place in the so-called normal region, and partly in the inverted region.     

The influence of hydration on the rotational barriers of glycine

The influence of a full first hydration shell on the energy barriers related to conformational changes of glycine has been studied by means of molecular orbital calculations. The energy optimized pathway is discussed and compared with that of the isolated molecule, evaluating the possibility of corotation of the hydration shell during conformational changes.

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Der Einfluß der Hydratation auf die Rotationsbarrieren von Glycin

Zusammenfassung Es wurde mit Hilfe einer Molekülorbitalrechnung der Einfluß der vollen ersten Hydrathülle auf Rotationsbarrieren bei Konformationsänderungen im Glycinmolekül untersucht. Es wird ein energieoptimierter Rotationsverlauf diskutiert und mit dem des freien Moleküls verglichen, wobei insbesondere die Möglichkeit einer Korotation der Hydrathülle beachtet wird.

     

The influence of Na+ on neighbouring hydrogen bonds of aliphatic amino acid

Summary The influence of Na⁺ on hydrogen bonds of the OH O and NH O type between an aliphatic amino acid (glycine zwitterion) and water is investigated byab initio calculations with minimal Gaussian basis sets. Distortion of the hydration shell caused by Na⁺, and interaction energies contributing to the over-all stabilization are discussed.

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Der Einfluß von Na⁺ auf die benachbarten Wasserstoffbindungen in aliphatischen Aminosäuren

Zusammenfassung Der Einfluß von Na⁺ auf die Wasserstoffbindungen vom OH O- und NH O-Typ in aliphatischen Aminosäuren (Glycin-Zwitterion) und Wasser wurde mittelsab initio Berechnungen mit einem minimalen Gausschen Basissatz untersucht. Die durch Na⁺-Ionen hervorgerufenen Verzerrungen der Hydratationsschale und die zur Gesamtstabilisierung beitragenden Wechselwir-kungsenergien werden diskutiert.