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Mar Drugs
2015 Feb 12;132:936-47. doi: 10.3390/md13020936.
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Conformational analysis of the oligosaccharides related to side chains of holothurian fucosylated chondroitin sulfates.
Gerbst AG
,
Dmitrenok AS
,
Ustyuzhanina NE
,
Nifantiev NE
.
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Anionic polysaccharides fucosylated chondroitin sulfates (FCS) from holothurian species were shown to affect various biological processes, such as metastasis, angiogenesis, clot formation, thrombosis, inflammation, and some others. To understand the mechanism of FCSs action, knowledge about their spatial arrangement is required. We have started the systematic synthesis, conformational analysis, and study of biological activity of the oligosaccharides related to various fragments of these types of natural polysaccharides. In this communication, five molecules representing distinct structural fragments of chondroitin sulfate have been studied by means of molecular modeling and NMR. These are three disaccharides and two trisaccharides containing fucose and glucuronic acid residues with one sulfate group per each fucose residue or without it. Long-range C-H coupling constants were used for the verification of the theoretical models. The presence of two conformers for both linkage types was revealed. For the Fuc-GlA linkage, the dominant conformer was the same as described previously in a literature as the molecular dynamics (MD) average in a dodechasaccharide FCS fragment representing the backbone chain of the polysaccharide including GalNAc residues. This shows that the studied oligosaccharides, in addition to larger ones, may be considered as reliable models for Quantitative Structure-Activity Relationship (QSAR) studies to reveal pharmacophore fragments of FCS.
Figure 1. Branched fragments of fucosylated chondroitin sulfates and synthetic oligosaccharides related to the knots.
Figure 2. Torsional angles describing a glycosidic linkage and the Karplus equation [17]. Angles φ and ψ are defined as H1–C1–O–Cx and C1–O–Cx–Hx correspondingly.
Figure 3. Sample confomational maps obtained by means of torsion scanning for Fuc–GlA (A) and Fuc–Fuc (B) linkages.
Figure 4. Molecular dynamics (MD) graphs and conformational plots obtained in the Solvent Accessible Surface Area (SASA) approximation for disaccharides 1–3 ordered from (A) to (C). Angles φ and ψ are defined as H1–C1–O–Cx and C1–O–Cx–Hx, respectively, for the sake of compatibility with the Karplus equation.
Figure 5. Conformational plots obtained in the SASA approximation for glycosidic linkages in structures 4 ((A), Fuc–GlA; (B), Fuc–Fuc) and 5 ((C), Fuc–GlA, (D), Fuc–Fuc). Angles φ and ψ are defined as H1–C1–O–Cx and C1–O–Cx–Hx, respectively, for the sake of compatibility with the Karplus equation.
Figure 6. Principal conformers of the Fuc(1→3)GlA linkage.
Figure 7. Torsional angles graph and conformational plots obtained using explicit water approximation for the fucosyl–glucuronide (A) and difucoside (B) fragments. Data are extracted from simulations of compound 4. Angles φ and ψ are defined as H1–C1–O–Cx and C1–O–Cx–Hx correspondingly for the sake of compatibility with the Karplus equation.
Figure 8. The dominant conformer of the Fuc(1→3)GlA linkage with the position of GalNAc residue introduction.
Figure 9. The NOE build-up graph at different mixing times for compound 4. The measured NOE values are for H1(Fuc)/H3(GlA) interaction.
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