Several inhibitors of the large regulatory enzyme glycogen phosphorylase (GP) have been studied in crystallographic and kinetic experiments. GP catalyses the first step in the phosphorylysis of glycogen to glucose-l-phosphate, which is utilized via glycolysis to provide energy to sustain muscle contraction and in the liver is converted to glucose. alpha-D-Glucose is a weak inhibitor of glycogen phosphorylase form b (GPb, K(i) = 1.7 mM) and acts as a physiological regulator of hepatic glycogen metabolism. Glucose binds to phosphorylase at the catalytic site and results in a conformational change that stabilizes the inactive T state of the enzyme, promoting the action of protein phosphatase 1 and stimulating glycogen synthase. It has been suggested that in the liver, glucose analogues with greater affinity for glycogen phosphorylase may result in a more effective regulatory agent. Several N-acetyl glucopyranosylamine derivatives have been synthesized and tested in a series of crystallographic and kinetic binding studies with GPb. The structural results of the bound enzyme-ligand complexes have been analysed together with the resulting affinities in an effort to understand and exploit the molecular interactions that might give rise to a better inhibitor. Comparison of the N-methylacetyl glucopyranosylamine (N-methylamide, K(i) = 0.032 mM) with the analogous beta-methylamide derivative (C-methylamide, K(i) = 0.16 mM) illustrate the importance of forming good hydrogen bonds and obtaining complementarity of van der Waals interactions. These studies also have shown that the binding modes can be unpredictable but may be rationalized with the benefit of structural data and that a buried and mixed polar/non-polar catalytic site poses problems for the systematic addition of functional groups. Together with previous studies of glucose analogue inhibitors of GPb, this work forms the basis of a training set suitable for three-dimensional quantitative structure-activity relationship studies. The molecules in the training set are void of problems and potential errors arising from the alignment and bound conformations of each of the ligands since the coordinates were those determined experimentally from the X-ray crystallographic refined ligand-enzyme complexes. The computational procedure described in this work involves the use of the program GRID to describe the molecular structures and the progam GOLPE to obtain the partial least squares regression model with the highest prediction ability. The GRID/GOLPE procedure performed using 51 glucose analogue inhibitors of GPb has good overall predictivity [standard deviation of error predictions (SDEP) = 0.98 and Q(2) = 0.76] and has shown good agreement with the crystallographic and kinetic results by reliably selecting regions that are known to affect the binding affinity.

alpha-D-Glucose is a weak inhibitor of glycogen phosphorylase b (Ki = 1.7 mM) and acts as a physiological regulator of hepatic glycogen metabolism. Glucose binds to phosphorylase at the catalytic site and results in a conformational change that stabilizes the inactive T state of the enzyme, promoting the action of protein phosphatase 1 and stimulating glycogen synthase. It has been suggested that, in the liver, glucose analogues with greater affinity for glycogen phosphorylase may result in a more effective regulatory agent. Several alpha- and beta-anhydroglucoheptonic acid derivatives and 1-deoxy-1-thio-beta-D-glucose analogues have been synthesized and tested in a series of crystallographic and kinetic binding studies with glycogen phosphorylase. The structural results of the bound enzyme-ligand complexes have been analyzed, together with the resulting affinities, in an effort to understand and exploit the molecular interactions that might give rise to a better inhibitor. This work has shown the following: (i) Similar affinities may be obtained through different sets of interactions. Specifically, in the case of the alpha- and beta-glucose-C-amides, similar Ki's (0.37 and 0.44 mM, respectively) are obtained with the alpha-anomer through interactions from the ligand via water molecules to the protein and with the beta-anomer through direct interaction from the ligand to the protein. Thus, hydrogen bonds through water can contribute binding energy similar to that of hydrogen bonds directly to the protein. (ii) Attempts to improve the inhibition by additional groups did not always lead to the expected result. The addition of nonpolar groups to the alpha-carboxamide resulted in a change in conformation of the pyranose ring from a chair to a skew boat and the consequent loss of favorable hydrogen bonds and increase in the Ki. (iii) The addition of polar groups to the alpha-carboxamide led to compounds with the chair conformation, and in the examples studied, it appears that hydration by a water molecule may provide sufficient stabilization to retain the chair conformation. (iv) The best inhibitor was N-methyl-beta-glucose-C-carboxamide (Ki = 0.16 mM), which showed a 46-fold improvement in Ki from the parent beta-D-glucose. The decrease in Ki may be accounted for by a single hydrogen bond from the amide nitrogen to a main-chain carbonyl oxygen, an increase in entropy through displacement of a water molecule, and favorable van der Waals contacts between the methyl substituent and nonpolar protein residues.(ABSTRACT TRUNCATED AT 250 WORDS)

The plant alkaloids castanospermine, dihydroxymethyldihydroxypyrrolidine and deoxynojirimycin have recently been shown to have potential anti-HIV activity [(1987) Proc. Natl. Acad. Sci. USA 84,8120-8124; (1987) Nature 330, 7477; Lancet i, 10251026]. They are thought to act by inhibiting a-glucosidase I, an enzyme involved in the processing of N-linked oligosaccharides on glycoproteins. We report here the relative efficacy of a spectrum of amino-sugar derivatives as inhibition of HIV cytopathicity. Several a-glucosidase inhibitors and a-fucosidase inhibitors were found to be active at concentrations which were non-cytotoxic.

No abstract

protocols that tailor the absorption spectrum of the active material. [1][2][3][4][5][6] While such efforts have resulted in a library of active materials, they have also presented challenges for commercial viability due to the different processes and costs associated with employing distinct active materials to display different colors. Their use has also resulted in varied performances among devices of different colors, adding to the difficulty for practical implementation. Furthermore, challenges in organic synthesis have limited the achievable types of color and their spectral purity. In this work, we introduce a strategy that enables a single active material that absorbs uniformly across the visible range to display different colors with high spectral purity and consistent device performances through the implementation of a color filtering (CF) electrode. The electrode consists of a Ag-TiO x -Ag Fabry-Perot (FP) resonant cavity, where the thickness of the TiO x layer determines the spectral position of the transmission peak and the inner Ag layer functions as an electrical contact. The electrode also functions as a mirror for all wavelengths of light except that within the resonant band (i.e., the spectral transparency window) of the CF. Therefore, light that has not been selectively transmitted may reflect back into the active material, contributing to additional charge generation. This implies that the short-circuit current density, which is largely a function of the optical absorption, must be higher for a CF-integrated OPV compared to a transparent OPV, under the condition that the two devices show similar peak transmission efficiencies.The use of photonic structures as optical filters in OPVs or inorganic solar cells has been previously reported in the form of distributed Bragg reflectors, [7][8][9] photonic arrays, [10][11][12] and plasmonic resonators. [13][14][15] While such filters enable various colors to be transmitted or reflected through tuning of the characteristic dimension of the filter components, in many cases they suffer from increased fabrication costs and duration because of the structural complexity. Moreover, photonic structures employing low-loss dielectrics exhibit poor electrical conductivity, precluding their use as an electrode. Finally, the structural anisotropy intrinsic to 1D or 3D photonic structures can result in asymmetric responses for light incident from above and below the device. Such behavior can complicate design schemes for creating bidirectional colored windows.Colorful, semitransparent organic photovoltaic cells (OPVs) are increasing in demand due to their applicability in aesthetically fashioned powergenerating windows. The traditional method of generating different colors in OPVs has been through employing different active materials exhibiting distinct absorption spectra. This can complicate fabrication processes for production and cause deviations in device performance among differently colored OPVs. Herein, semitransparent and colorful OPVs with a single broadban...

Semitransparent colorful organic solar cells (OSC) provide exciting opportunities for harnessing sunlight as colored windows. Previously, color filter (CF) electrodes on (OSC) were demonstrated via vacuum-deposition techniques, resulting in deposition-induced damage. Thus, we present CF integrated organic photovoltaics (CF-OPVs) using solution-processed TiO2–AcAc as the dielectric component. The noninvasive processing substantially expands the range of usable active materials, allowing the device to display pure and vibrant colors that are independent of the inherent color of the active material and show superior optical and photovoltaic characteristics. These results provide practical pathways to realizing colored semitransparent solar cells.

Single particle Mie calculations of near micron-sized TiO particles predict strong light scattering dominating the visible range that would give rise to a white appearance. We demonstrate that a polydisperse collection of these "white" particles can result in the generation of visible colors through ensemble scattering. The weighted averaging of the scattering over the particle size distribution modifies the sharp, multiple, high order scattering modes from individual particles into broad variations in the collective extinction. These extinction variations are apparent as visible colors for particles suspended in organic solvent at low concentration, or for a monolayer of particles supported on a transparent substrate viewed in front of a white light source. We further exploit the color variations on optical sensitivity to the surrounding environment to promote micron-sized TiO particles as stable and robust agents for detecting the optical index of homogeneous media with high contrast sensitivities. Such distribution-modulated scattering properties provide TiO particles an intriguing opportunity to impart color and optical sensitivity to their widespread electronic and chemical platforms such as antibacterial windows, catalysis, photocatalysis, optical sensors, and photovoltaics.

No abstract