Dextran Graft Copolymers: Synthesis, Properties and Applications

Ōnishi, Yasuhiko; Eshita, Yuki; Mizuno, Masaaki

doi:10.1007/978-3-642-36566-9_6

Cited by 4 publications

(7 citation statements)

References 49 publications

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“…These values offer valuable information about the influence of electron density distribution on chemical behavior and interactions. Hardness (η) values are crucial for understanding a compound’s resistance to deformation or changes in electron density upon electron addition or removal [ 39 ]. C6 showed the highest hardness at 0.219, indicating a relatively rigid molecular structure with low electron deformability.…”

Section: Discussionmentioning

confidence: 99%

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Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease

Owoloye,

Olubode,

Ogunleye

et al. 2023

Preprint

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Background Sickle cell disease (SCD) poses a significant health challenge and therapeutic approaches often target fetal hemoglobin (HbF) to ameliorate symptoms. Hydroxyurea, a current therapeutic option for SCD, has shown efficacy in increasing HbF levels. However, concerns about myelosuppression and thrombocytopenia necessitate the exploration of alternative compounds. Heme-regulated inhibitor (HRI) presents a promising target for pharmacological intervention in SCD due to its association with HbF modulation. This study systematically screened compounds for their potential inhibitory functions against HRI. Methods Small-molecule compounds from 17 plants commonly utilized in traditional SCD management were subjected to in silico screening against HRI. Molecular docking was performed, and free binding energy calculations were determined using molecular mechanics with generalized born and surface area (MMGBSA). The lead compounds were subjected to molecular dynamics simulation at 100 ns. Computational quantum mechanical modelling of the lead compounds was subsequently performed. We further examined the pharmacodynamics, pharmacokinetic and physiological properties of the identified compounds. Results Five potential HRI inhibitors, including kaempferol-3-(2G-glucosyrutinoside), epigallocatechin gallate, tiliroside, myricetin-3-O-glucoside, and cannabiscitrin, with respective docking scores of -16.0, -12.17, -11.37, -11.56 and 11.07 kcal/mol, were identified. The MMGBSA analysis of the complexes yielded free-binding energies of -69.76, -71.17, -60.44, 53.55, and − 55 kcal/mol, respectively. The identified leads were stable within HRI binding pocket for the duration of 100 ns simulation. Conclusions The study successfully identified five phytoligands with potential inhibitory effects on HRI, opening avenues for their use as modulators of HbF in SCD patients. This finding holds promise for advancing treatment strategies in SCD. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds.

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Section: Discussionmentioning

confidence: 99%

“…Conversely, C5 had the lowest hardness at 0.069, suggesting a more flexible molecular structure. The hardness values of C1 to C4 fell within this range, indicating varying degrees of resistance to electron perturbations [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease

Owoloye,

Olubode,

Ogunleye

et al. 2023

Preprint

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“…The stability of the enzyme-substrate complex is shown as 1/K m , and larger for DDMC/PTX complex than for PTX alone, corresponding to [S] 0 n >>K m . From our previous report [14,[25][26][27], the DDMC/ PTX complex may promote enzymically tubulin polymerization that can be expressed using Michaelis-Menten kinetics added the Hill coefficient [33]. These phenomena also show the supramolecular properties of the DDMC/ PTX complex.…”

Section: Michaelis-menten Kineticsmentioning

confidence: 97%

“…It has been reported that DDMC is superior to other transfection agents with safety efficacy by autoclaved as a non-viral carrier for gene introduction [16][17][18][19][20][21][22][23][24]. On the other hand, the paclitaxel is well known as a strong anti-cancer drug to introduce cancer cells to apoptosis in stabilization of tubulin (i.e., tubulin polymerization) [14,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

“…DEAE-dextran-MMA copolymer (2-diethylaminoethyl-dextran-methyl methacrylate graft copolymer (DDMC)) was obtained by graft-polymerization of MMA onto DEAE-dextran in water [11][12][13][14]. The resulting DDMC consists of "hairy" nanoparticles having a hydrophilic-hydrophobic microseparated domain with an amphiphilic domain (DEAE-dextran) and a hydrophobic domain (PMMA) that form a polymer micelle [15].…”

Section: Introductionmentioning

confidence: 99%

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Medicinal facilities to B16F10 melanoma cells for distant metastasis control with a supramolecular complex by DEAE-dextran-MMA copolymer/paclitaxel

Eshita

Onishi³

et al. 2015

Drug Deliv. and Transl. Res.

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The resistance of cancer cells to chemotherapeutic drugs (MDR) is a major problem to be solved. A supramolecular DEAE-dextran-MMA copolymer (DDMC)/paclitaxel (PTX) complex was obtained by using PTX as the guest and DDMC as the host having 50-300 nm in diameter. The drug resistance of B16F10 melanoma cells to paclitaxel was observed, but there is no drug resistance of melanoma cells to the DDMC/PTX complex in vitro. The cell death rate was determined using Michaelis-Menten kinetics, as the DDMC/PTX complex promoted allosteric supramolecular reaction to tubulin. The DDMC/PTX complex showed a very superior anti-cancer activity to paclitaxel alone in vivo. The median survival time (MST) of the saline, PTX, DDMC/PTX4 (particle size, 50 nm), and DDMC/PTX5 (particle size, 290 nm) groups were 120 h (T/C, 1.0), 176 h (T/C, 1.46), 328 h (T/C, 2.73), and 280 h (T/C, 2.33), respectively. The supramolecular DDMC/PTX complex showed the twofold effectiveness of PTX alone (p < 0.036). Histochemical analysis indicated that the administration of DDMC/PTX complex decreased distant metastasis and increased the survival of mice. A mouse of DDMC/PTX4 group in vivo was almost curing after small dermatorrhagia owing to its anti-angiogenesis, and it will be the hemorrhagic necrotic symptom of tumor by the release of "tumor necrosis factor alpha (TNF-α)" cytokine. As the result, the medicinal action of the DDMC/PTX complex will suppress the tumor-associated action of M2 macrophages and will control the metastasis of cancer cells.

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Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease

Owoloye,

Olubode,

Ogunleye

et al. 2024

Journal of Biomolecular Structure and Dynamics

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BackgroundSickle cell disease (SCD) poses a signi cant health challenge and therapeutic approaches often target fetal hemoglobin (HbF) to ameliorate symptoms. Hydroxyurea, a current therapeutic option for SCD, has shown e cacy in increasing HbF levels. However, concerns about myelosuppression and thrombocytopenia necessitate the exploration of alternative compounds.Heme-regulated inhibitor (HRI) presents a promising target for pharmacological intervention in SCD due to its association with HbF modulation. This study systematically screened compounds for their potential inhibitory functions against HRI. MethodsSmall-molecule compounds from 17 plants commonly utilized in traditional SCD management were subjected to in silico screening against HRI. Molecular docking was performed, and free binding energy calculations were determined using molecular mechanics with generalized born and surface area (MMGBSA). The lead compounds were subjected to molecular dynamics simulation at 100 ns. Computational quantum mechanical modelling of the lead compounds was subsequently performed. We further examined the pharmacodynamics, pharmacokinetic and physiological properties of the identi ed compounds. ResultsFive potential HRI inhibitors, including kaempferol-3-(2G-glucosyrutinoside), epigallocatechin gallate, tiliroside, myricetin-3-Oglucoside, and cannabiscitrin, with respective docking scores of -16.0, -12.17, -11.37, -11.56 and 11.07 kcal/mol, were identi ed. The MMGBSA analysis of the complexes yielded free-binding energies of -69.76, -71.17, -60.44, 53.55, and − 55 kcal/mol, respectively. The identi ed leads were stable within HRI binding pocket for the duration of 100 ns simulation. ConclusionsThe study successfully identi ed ve phytoligands with potential inhibitory effects on HRI, opening avenues for their use as modulators of HbF in SCD patients. This nding holds promise for advancing treatment strategies in SCD. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds.

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Dextran Graft Copolymers: Synthesis, Properties and Applications

Cited by 4 publications

References 49 publications

Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease

Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease

Medicinal facilities to B16F10 melanoma cells for distant metastasis control with a supramolecular complex by DEAE-dextran-MMA copolymer/paclitaxel

Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease

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