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Glucose analogue inhibitors of glycogen phosphorylase: from crystallographic analysis to drug prediction using GRID force-field and GOLPE variable selection (1995)

Watson, K. A. ; Mitchell, E. P. ; Johnson, L. N. ; [et al.]

Copenhagen : International Union of Crystallography (IUCr)

Acta crystallographica 51 (1995), S. 458-472

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ISSN: 1399-0047

Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001

Topics: Chemistry and Pharmacology , Geosciences , Physics

Notes: 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. α-D-Glucose is a weak inhibitor of glycogen phosphorylase form b (GPb, 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 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, Ki = 0.032 mM) with the analogous β-methylamide derivative (C-methylamide, Ki = 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 Q2 = 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.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1107/S090744499401348X

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A scanning electron microscopic study of the growth of hydroxyapatite crystals (1972)

Meyer, J. L. ; Eick, J. D. ; Nancollas, G. H. ; [et al.]

Springer

Calcified tissue international 10 (1972), S. 91-102

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ISSN: 1432-0827

Keywords: Hydroxyapatite ; Calcification ; Phases ; Growth ; Microscopy

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Medicine , Physics

Description / Table of Contents: Résumé La croissance cristalline de l'hydroxyleapatite à 25° et à pH constant de 7.4 a été étudiée à l'aide du microscope électronique à balayage. La technique reproductible de croissance par ensemencement à partir de solutions stables sursaturées est utilisée efficacement pour produire des échantillons de minéral à divers stades distincts de croissance. Des changements de phase sont observés avec le progrès de la croissance; ils correspondent dans le temps avec les résultats cinétiques obtenus antérieurement. Un essai de rationalisation est tenté à la lumière des mécanismes proposés pour la formation d'hydroxyleapatite dans des conditionsin vivo.

Abstract: Zusammenfassung Das Kristallwachstum von Hydroxyapatit bei 25° und einem konstanten pH von 7,4 wurde mit Hilfe eines Raster-Elektronenmikroskopes studiert. Die reproduzierbare Technik des Keimwachstums aus stabilen übersättigten Lösungen wurde mit Erfolg verwendet, um Mineralproben in verschiedenen bestimmten Stadien des Wachstums zu erhalten. Phasenveränderungen wurden beim fortschreitenden Wachstum beobachtet, und diese stimmten zeitlich gut überein mit kinetischen Resultaten, über welche früher berichtet wurde. Es wurde versucht, diese Beobachtungen zu erklären in Anbetracht von Mechanismen, welche für die Bildung von Hydroxyapatit unterin vivo-Bedingungen vorgeschlagen wurden.

Notes: Abstract The crystal growth of hydroxyapatite at 25° and at a constant pH of 7.4 has been studied with the aid of a scanning electron microscope. The reproducible technique of seeded growth from stable supersaturated solutions was used effectively to produce samples of the mineral at various distinct stages of growth. Phase changes were observed as the growth proceeded and these corresponded favorably in time with kinetic results reported earlier. An attempt was made to rationalize the observations in light of mechanisms proposed for the formation of hydroxyapatite under conditions foundin vivo.