Molecular dynamics simulation of a decasaccharide fragment of heparin in aqueous solution

Verli, Hugo; Guimarães, Jorge A.

doi:10.1016/j.carres.2003.09.026

Cited by 68 publications

(100 citation statements)

References 32 publications

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“…15 The resultant topology was further submitted to refinements, for example, atomic charges and improper dihedrals in order to define the conformational state of IdoA residue ( 1 C 4 or 2 S 0 ). 7 2.1.3. Atomic charge calculations.…”

Section: Introductionmentioning

confidence: 98%

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Molecular dynamics and atomic charge calculations in the study of heparin conformation in aqueous solution

Becker¹,

Guimarães²,

Verli³

2005

Carbohydrate Research

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Section: Introductionmentioning

confidence: 98%

“…1) structure has already been described. 7 Briefly the heparin fragment was retrieved from protein data bank under code 1HPN. 8 This dodecasaccharide was reduced to a decasaccharide structure and then submitted to the PRODRG PRODRG server.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics and atomic charge calculations in the study of heparin conformation in aqueous solution

Becker¹,

Guimarães²,

Verli³

2005

Carbohydrate Research

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“…[14][15][16][17][18][19][20][21] Initially, all the nonpolar hydrogens were removed and only polar hydrogens were kept. The partial charges of SC161, which has polar hydrogens intact, were obtained by ab initio calculation.…”

Section: Experimental and Computational Methods Molecular Dynamics (Md)mentioning

confidence: 99%

Discovery of Novel Anticancer Compounds Based on a Quinoxalinehydrazine Pharmacophore

et al. 2008

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Quinoxalinehydrazines represent a novel class of compounds with excellent potency in a panel of cancer cell lines. A prototype compound, SC144, showed significant in vivo efficacy in mice xenograft models of human breast cancer cells. The subsequent structure-activity relationship study resulted in the discovery of SC161 with better potency in cancer cell lines. Further exploring the possible conformational space by a 10 ns molecular dynamics simulation as presented herein, resulted in various pharmacophore orientations. The trajectory analysis indicated that in most of the simulation time, the molecule stays favorably in a compact planarlike orientation. We therefore built a pharmacophore model based on the cluster containing the highest number of frames to represent the most probable orientation. The model was used to screen a subset of our small molecule database containing 350,000 compounds. We selected 35 compounds for the initial cytotoxicity screen. Seventeen compounds belonging to oxadiazolopyrazine and quinoline class displayed cytotoxicity in various cancer cell lines. Five of them, compounds 2, 6, 15, 16, and 19, all bearing an oxadiazolopyrazine scaffold, showed IC(50) values <3 muM in certain tumor cell lines. The most potent compound, 2, showed IC(50) values <2 muM in HCT116 p53(+/+), HCT116 p53(-/-), and HEY cells, and 8 muM in NIH3T3 cells. This study shows that conformational sampling of a lead small molecule followed by representative pharmacophore model development is an efficient approach for the rational design of novel anticancer agents with similar or better potency than the original lead but with different physicochemical properties.

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“…These topologies were supplied with Löwdin HF/6 -31G** atomic charges (23,24) and submitted to conformational analysis by varying the and dihedral angles from Ϫ180 to 180°, with a 30°step, in a total of 144 conformers for each linkage. Each conformation was further refined in a 20-ps molecular dynamics at 10 K, with an integration step of 0.5 fs (25).…”

Section: Extraction Of Sulfated Galactan From Egg Jelly Of Sea Urchins-mentioning

confidence: 99%

“…The relative stabilities of the conformations were used to construct relaxed energy contour plots. The minimum energy conformations described in these plots were submitted to 0.1 s molecular dynamics (MD) simulations in aqueous solutions using the SPC water model (26) following a protocol previously described (23,24,27). A triclinic water box under periodic boundary conditions was employed using a 10-Å minimum distance from solute to the box faces.…”

Section: Extraction Of Sulfated Galactan From Egg Jelly Of Sea Urchins-mentioning

confidence: 99%

A Unique 2-Sulfated β-Galactan from the Egg Jelly of the Sea Urchin Glyptocidaris crenularis

Castro

Pomin

Santos

et al. 2009

Journal of Biological Chemistry

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Sulfated polysaccharides from the egg jelly of sea urchins act as species-specific inducers of the sperm acrosome reaction, which is a rare molecular mechanism of carbohydrate-induced signal-transduction event in animal cells. The sea urchin polysaccharides differ in monosaccharide composition (L-fucose or L-galactose), glycosylation, and sulfation sites, but they are always in the ␣-anomeric configuration. Herein, structural analysis of the polysaccharide from the sea urchin Glyptocidaris crenularis surprisingly revealed a unique sulfated ␤-D-galactan composed by (3-␤-D-Galp-2(OSO 3 )-133-␤-D-Galp-1) n repeating units. Subsequently, we used the G. crenularis galactan to compare different 2-sulfated polysaccharides as inducers of the acrosome reaction using homologous and heterologous sperm. We also tested the effect of chemically over-sulfated galactans. Intriguingly, the anomeric configuration of the glycosidic linkage rather than the monosaccharide composition (galactose or fucose) is the preferential structural requirement for the effect of these polysaccharides on sea urchin fertilization. Nuclear magnetic resonance and molecular dynamics indicate that sulfated ␣-galactan or ␣-fucan have less dynamic structural behavior, exhibiting fewer conformational populations, with an almost exclusive conformational state with glycosidic dihedral angles ⌽/⌿ ‫؍‬ ؊102°/131°. The preponderant conformer observed in the sulfated ␣-galactan or ␣-fucan is not observed among populations in the ␤-form despite its more flexible structure in solution. Possibly, a proper spatial arrangement is required for interaction of the sea urchin-sulfated polysaccharides with the specific sperm receptor.The evolution of barriers to inter-specific hybridization is a crucial step in the fertilization of free-spawning marine invertebrates. In sea urchins the molecular recognition between sperm and egg ensures species recognition. The jelly coat surrounding sea urchin eggs is not a simple accessory structure; it is considerably complex on a molecular level and intimately involved in gamete recognition. It contains sulfated polysaccharides, sialoglycans, and peptides.Structural changes in the sulfated polysaccharide from the egg jelly of sea urchins modulate cell-cell recognition and species specificity leading to exocytosis of the acrosomal vesicle, the acrosome reaction. This is a crucial event for the recognition between male and female gametes, leading to the fertilization success, and is also what prevents intercrosses. The sulfated polysaccharide from the egg jelly recognizes its specific receptor present in the sperm. Apart from the sialoglycans that act in synergy with the sulfated polysaccharides, other components of the egg jelly do not possess acrosome reaction-inducing activity (1). The sulfated polysaccharide-mediated mechanism of sperm-egg recognition co-exists with that of bindin and its receptor in the egg (2-4).The sulfated polysaccharides from sea urchin show speciesspecific structures composed of repetitive units (mono-, tri-, ...

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Molecular dynamics simulation of a decasaccharide fragment of heparin in aqueous solution

Cited by 68 publications

References 32 publications

Molecular dynamics and atomic charge calculations in the study of heparin conformation in aqueous solution

Molecular dynamics and atomic charge calculations in the study of heparin conformation in aqueous solution

Discovery of Novel Anticancer Compounds Based on a Quinoxalinehydrazine Pharmacophore

A Unique 2-Sulfated β-Galactan from the Egg Jelly of the Sea Urchin Glyptocidaris crenularis

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