An extensive crystal survey of the Cambridge Structural Database has been carried out to provide hydrogen-bond data for use in drug-design strategies. Previous crystal surveys have generated 1D frequency distributions of hydrogen-bond distances and angles, which are not sufficient to model the hydrogen bond as a ligand-receptor interaction. For each hydrogen-bonding group of interest to the drug designer, geometric hydrogen-bond criteria have been derived. The 3D distribution of complementary atoms about each hydrogen-bonding group has been ascertained by dividing the space about each group into bins of equal volume and counting the number of observed hydrogen-bonding contacts in each bin. Finally, the propensity of each group to form a hydrogen bond has been calculated. Together, these data can be used to predict the potential site points with which a ligand could interact and therefore could be used in molecular-similarity studies, pharmacophore query searching of databases, or de novo design algorithms.
Summary. Standard stereological methods have been used to determine the morphometric parameters of organelles contained in the fi-eells of mouse pancreas. Sectioned material from ten islets was analysed at three levels of magnification in the electron microscope. Quantitative data was obtained about the volume number and surface area of the various cytological components and was expressed as density per cm a of tissue and as absolute dimensions for the average fl-eell. The organelles studied were the nucleus, cytoplasmic ground substance, rough and smooth endoplasmie reticulum, the ribosomes, mitoehondria, fl-granules and microtubules.
SUMMARY1. Intracellular recording of the transmembrane potential in mouse pancreatic cells revealed a membrane potential of -20-1 + 0-8 mV for islet cells and -41-2 + 1P4 mV for acinar cells.2. The membrane potential of islet cells was glucose dependent and in the absence of glucose the cells hyperpolarized to -32-7 mV; with glucose 27-7 mm they depolarized to -16-1 mV.3. Above a threshold concentration of glucose (4 mM) small action potentials of amplitude 1-4 mV were induced in islet cells. The percentage of cells impaled exhibiting action potentials reached a maximum of 80 % at 27-7 mm glucose.4. Mannose 16-6 mm was similar to glucose in its ability to induce action potential discharge in islet cells.5. 2,4-Dinitrophenol (0.25 mM) hyperpolarized islet cells and blocked electrical activity induced by glucose 11 1 mM.6. Adrenaline (1,uM) completely blocked glucose-induced electrical activity but without altering the membrance potential. 7. The origin and functional significance of glucose-induced electrical activity in islet cells is discussed in relation to insulin secretion.
Water is known to play an important role in the recognition and stabilization of the interaction between a ligand and its site. This has important implications for drug design. Analyses of 19 high-resolution crystal structures of protein-ligand complexes reveal the multiple hydrogen-bonding feature of water molecules mediating protein-ligand interactions. Most of the water molecules (nearly 80%) involved in bridging the protein and the ligand can make three or more hydrogen bonds when distance and bond angles are used as criteria to define hydrogen-bonding interactions. Isotropic B-factors have been used to take into account the mobility of water molecules. The water molecules at binding sites bridge the protein and ligand, and interact with other water molecules to form a complex network of interconnecting hydrogen bonds. Some water molecules at the site do not directly bridge between the protein and the ligand, but may contribute indirectly to the stability of the complex by holding bridging water molecules in the right position through a network of hydrogen bonds. These water networks are probably crucial for the stability of the protein-ligand complex and are important for any site-directed drug design strategies.
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