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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張書瑋 | |
| dc.contributor.author | Yi-Ching Lai | en |
| dc.contributor.author | 賴以敬 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:24:57Z | - |
| dc.date.available | 2021-08-16 | |
| dc.date.copyright | 2018-08-16 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-15 | |
| dc.identifier.citation | 1. Laurent, T.C., U.B. Laurent, and J.R.E. Fraser, The structure and function of hyaluronan: an overview. Immunology and cell biology, 1996. 74(2): p. A1.
2. Toole, B., Hyaluronan and its binding proteins, the hyaladherins. Current opinion in cell biology, 1990. 2(5): p. 839-844. 3. Johnson, P. and B. Ruffell, CD44 and its role in inflammation and inflammatory diseases. Inflammation & Allergy-Drug Targets (Formerly Current Drug Targets-Inflammation & Allergy), 2009. 8(3): p. 208-220. 4. Bourguignon, L.Y. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. in Seminars in cancer biology. 2008. Elsevier. 5. Sheehan, J.K. and E.D.T. Atkins, X-ray fibre diffraction study of conformational changes in hyaluronate induced in the presence of sodium, potassium and calcium cations. International Journal of Biological Macromolecules, 1983. 5(4): p. 215-221. 6. Sheehan, J.K., C. Arundel, and C.F. Phelps, Effect of the cations sodium, potassium and calcium on the interaction of hyaluronate chains: a light scattering and viscometric study. International Journal of Biological Macromolecules, 1983. 5(4): p. 222-228. 7. Almond, A., P.L. DeAngelis, and C.D. Blundell, Hyaluronan: The Local Solution Conformation Determined by NMR and Computer Modeling is Close to a Contracted Left-handed 4-Fold Helix. Journal of Molecular Biology, 2006. 358(5): p. 1256-1269. 8. Alessandro, D., et al., Solution structure of hyaluronic acid oligomers by experimental and theoretical NMR, and molecular dynamics simulation. Biopolymers, 2001. 59(6): p. 434-445. 9. Almond, A., A. Brass, and J.K. Sheehan, Dynamic exchange between stabilized conformations predicted for hyaluronan tetrasaccharides: comparison of molecular dynamics simulations with available NMR data. Glycobiology, 1998. 8(10): p. 973-980. 10. Verma, R.P. and C. Hansch, Matrix metalloproteinases (MMPs): Chemical–biological functions and (Q)SARs. Bioorganic & Medicinal Chemistry, 2007. 15(6): p. 2223-2268. 11. Kessenbrock, K., V. Plaks, and Z. Werb, Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 2010. 141(1): p. 52-67. 12. Zitka, O., et al., Matrix Metalloproteinases. Current Medicinal Chemistry, 2010. 17(31): p. 3751-3768. 13. McCawley, L.J. and L.M. Matrisian, Matrix metalloproteinases: they're not just for matrix anymore! Current opinion in cell biology, 2001. 13(5): p. 534-540. 14. Alexander, C.M. and Z. Werb, Extracellular matrix degradation, in Cell biology of extracellular matrix. 1991, Springer. p. 255-302. 15. Birkedal-Hansen, H., Proteolytic remodeling of extracellular matrix. Current opinion in cell biology, 1995. 7(5): p. 728-735. 16. Rowsell, S., et al., Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor. Journal of molecular biology, 2002. 319(1): p. 173-181. 17. Vijayababu, M., et al., Quercetin downregulates matrix metalloproteinases 2 and 9 proteins expression in prostate cancer cells (PC-3). Molecular and cellular biochemistry, 2006. 287(1-2): p. 109-116. 18. Whittaker, M., et al., Design and therapeutic application of matrix metalloproteinase inhibitors. Chemical reviews, 1999. 99(9): p. 2735-2776. 19. Sternlicht, M.D. and Z. Werb, How matrix metalloproteinases regulate cell behavior. Annual review of cell and developmental biology, 2001. 17(1): p. 463-516. 20. Egeblad, M. and Z. Werb, New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer, 2002. 2(3): p. 161. 21. Wiseman, B.S., et al., Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. The Journal of cell biology, 2003. 162(6): p. 1123-1133. 22. Puerta, D.T., J.A. Lewis, and S.M. Cohen, New beginnings for matrix metalloproteinase inhibitors: identification of high-affinity zinc-binding groups. Journal of the American Chemical Society, 2004. 126(27): p. 8388-8389. 23. Cheng, F., et al., Quantum chemistry study on the interaction of the exogenous ligands and the catalytic zinc ion in matrix metalloproteinases. The Journal of Physical Chemistry B, 2002. 106(17): p. 4552-4559. 24. Chen, J.M., et al., Structure-based design of a novel, potent, and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design. Journal of the American Chemical Society, 2000. 122(40): p. 9648-9654. 25. Aureli, L., et al., Structural bases for substrate and inhibitor recognition by matrix metalloproteinases. Current medicinal chemistry, 2008. 15(22): p. 2192-2222. 26. Tandon, A. and S. Sinha, Structural insights into the binding of MMP9 inhibitors. Bioinformation, 2011. 5(8): p. 310. 27. Skiles, J.W., N.C. Gonnella, and A.Y. Jeng, The design, structure, and therapeutic application of matrix metalloproteinase inhibitors. Current medicinal chemistry, 2001. 8(4): p. 425-474. 28. Rao, B.G., Recent developments in the design of specific matrix metalloproteinase inhibitors aided by structural and computational studies. Current pharmaceutical design, 2005. 11(3): p. 295-322. 29. Coussens, L.M., B. Fingleton, and L.M. Matrisian, Matrix metalloproteinase inhibitors and cancer—trials and tribulations. Science, 2002. 295(5564): p. 2387-2392. 30. Babine, R.E. and S.L. Bender, Molecular recognition of protein− ligand complexes: Applications to drug design. Chemical reviews, 1997. 97(5): p. 1359-1472. 31. Buehler, M.J., Atomistic modeling of materials failure. 2008: Springer Science & Business Media. 32. Guvench, O., et al., CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate–protein modeling. Journal of chemical theory and computation, 2011. 7(10): p. 3162-3180. 33. Vanommeslaeghe, K. and A.D. MacKerell Jr, Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing. Journal of chemical information and modeling, 2012. 52(12): p. 3144-3154. 34. Vanommeslaeghe, K., E.P. Raman, and A.D. MacKerell Jr, Automation of the CHARMM General Force Field (CGenFF) II: assignment of bonded parameters and partial atomic charges. Journal of chemical information and modeling, 2012. 52(12): p. 3155-3168. 35. Meng, X.-Y., et al., Molecular docking: a powerful approach for structure-based drug discovery. Current computer-aided drug design, 2011. 7(2): p. 146-157. 36. McConkey, B.J., V. Sobolev, and M. Edelman, The performance of current methods in ligand–protein docking. Current Science, 2002: p. 845-856. 37. Jorgensen, W.L., The many roles of computation in drug discovery. Science, 2004. 303(5665): p. 1813-1818. 38. Kitchen, D.B., et al., Docking and scoring in virtual screening for drug discovery: methods and applications. Nature reviews Drug discovery, 2004. 3(11): p. 935. 39. Gohlke, H. and G. Klebe, Approaches to the description and prediction of the binding affinity of small‐molecule ligands to macromolecular receptors. Angewandte Chemie International Edition, 2002. 41(15): p. 2644-2676. 40. Cross, J.B., et al., Comparison of several molecular docking programs: pose prediction and virtual screening accuracy. Journal of chemical information and modeling, 2009. 49(6): p. 1455-1474. 41. Isralewitz, B., M. Gao, and K. Schulten, Steered molecular dynamics and mechanical functions of proteins. Current opinion in structural biology, 2001. 11(2): p. 224-230. 42. Izrailev, S., et al., Steered molecular dynamics, in Computational molecular dynamics: challenges, methods, ideas. 1999, Springer. p. 39-65. 43. Phillips, J.C., et al., Scalable molecular dynamics with NAMD. Journal of computational chemistry, 2005. 26(16): p. 1781-1802. 44. Belviso, B.D., et al., Structure of matrix metalloproteinase-3 with a platinum-based inhibitor. Chemical Communications, 2013. 49(48): p. 5492-5494. 45. Trott, O. and A.J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry, 2010. 31(2): p. 455-461. 46. Sweetman, A., et al., Mapping the force field of a hydrogen-bonded assembly. Nature communications, 2014. 5: p. 3931. 47. Heldin, P., et al., Importance of hyaluronan-CD44 interactions in inflammation and tumorigenesis. Connective tissue research, 2008. 49(3-4): p. 215-218. 48. Jamison II, F.W., et al., Mechanism of binding site conformational switching in the CD44–hyaluronan protein–carbohydrate binding interaction. Journal of molecular biology, 2011. 406(4): p. 631-647. 49. Banerji, S., et al., Structures of the Cd44–hyaluronan complex provide insight into a fundamental carbohydrate-protein interaction. Nature structural and molecular biology, 2007. 14(3): p. 234. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70262 | - |
| dc.description.abstract | Hyaluronan (HA) is a natural linear polysaccharide composed of disaccharide repeating units. HA is widely used in cosmetics and skin care product due to its excellent moisturizing ability. Recently, a novel derivative of hyaluronan, named Hya-HEAL+, has been synthesized and shown to have great ability in anti-aging skin care product applications. The novel derivative of hyaluronan (Hya-HEAL+) is modified with histidine side chain and hydrophobic group with a 30% to 50% degree of substitution of repeating units. Experimental results have shown that the novel derivative of hyaluronan (Hya-HEAL+) can effectively inhibit MMP-1, 3, 2, 9 (matrix metalloproteinase) which are enzymes that degrade collagen. By inhibiting the activity of MMP, the Hya-HEAL+ prevents the decomposition of collagen and shows an anti-aging effect. However, the molecular mechanisms of the inhabitation of MMP are still not clear.
In this study, we investigate the molecular structure of Hya-HEAL+ and the molecular mechanisms of the inhibitory effect of Hya-HEAL+ on MMP through a full atomistic simulation approach. From nano-scale, we find that the hydrophobic group on Hya-HEAL+ is responsible for the structural difference between HA and Hya-HEAL+. Hya-HEAL+ interacts with MMP through hydrogen bonds, hydrophobic group and chelation of the active site zinc. The hydrophobic group increases the binding ability. Hya-HEAL+ binds to MMP and effectively prevents collagen degradation to achieve an anti-aging effect. This study provides fundamental insights into the conformations of Hya-HEAL+ and the binding pose of Hya-HEAL+ to MMP and help explaining the molecular properties and molecular mechanisms of the inhibitory effect of Hya-HEAL+ on MMP. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:24:57Z (GMT). No. of bitstreams: 1 ntu-107-R05521234-1.pdf: 4162327 bytes, checksum: 9f2dd81470c7347ce1363079f69a8590 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 目錄
口試委員會審定書 ii 致謝 iii 中文摘要 iv Abstract v 圖目錄 vi 表目錄 ix 目錄 1 第一章 緒論 3 1.1研究背景 3 1.2文獻回顧 5 1.2.1 玻尿酸之分子結構 5 1.2.2 MMP蛋白質與其抑制劑之發展 5 1.3研究目的 8 1.4研究大綱 8 第二章 研究方法 9 2.1分子動力模擬(Molecular Dynamics Simulation, MD) 9 2.1.1力場 10 2.2 分子嵌合模擬(Molecular docking simulation) 12 2.3 Steered Molecular Dynamics(SMD) 13 2.3.1等速度拉伸法 13 2.4模型建構及模擬流程 15 2.4.1玻尿酸與Hya-HEAL+模型建構及模擬流程 15 2.4.2MMP模型建構及模擬流程 17 2.5 分析方法 20 2.5.1 配糖鍵 20 2.5.2氫鍵 20 2.5.3End to end distance 21 第三章 玻尿酸與Hya-HEAL+之分子結構比較 22 3.1分析結果 23 3.1.1 配糖鍵 23 3.1.2 End to end distance 26 3.1.3氫鍵 28 3.1.4含氮基團之構型 37 3.1.5接枝鍊之構型 39 3.2結果討論 41 第四章 Hya-HEAL+對MMP酵素之抑制機制 42 4.1分析結果 43 4.1.1 Hya-HEAL+與MMP之Hydrophobic interaction 43 4.1.2 玻尿酸與Hya-HEAL+對MMP之氫键 45 4.1.3 玻尿酸和Hya-HEAL+與MMP之螯合 50 4.1.4 MMP之鋅離子降解區之構型 52 4.1.5 Steered Molecular Dynamics(SMD)之結果 54 4.2結果討論 56 第五章 結論與未來研究方向 57 附錄一 58 附錄二 63 參考文獻 70 | |
| dc.language.iso | zh-TW | |
| dc.subject | 玻尿酸 | zh_TW |
| dc.subject | Hya-HEAL+ | zh_TW |
| dc.subject | 分子動力模擬 | zh_TW |
| dc.subject | 分子嵌合 | zh_TW |
| dc.subject | 抗老化 | zh_TW |
| dc.subject | 金屬基質蛋白? | zh_TW |
| dc.subject | anti-aging | en |
| dc.subject | Hyaluronan | en |
| dc.subject | matrix metalloproteinase | en |
| dc.subject | Hya-HEAL+ | en |
| dc.subject | molecular docking | en |
| dc.subject | molecular dynamics | en |
| dc.title | 以分子動力模擬探討改質玻尿酸抑制基質金屬蛋白酶活性之分子機制 | zh_TW |
| dc.title | The molecular inhibitory effect of a novel derivative of hyaluronan on MMPs activities: A molecular dynamics approach | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 徐善慧,施亭宇,陳俊杉 | |
| dc.subject.keyword | 玻尿酸,Hya-HEAL+,分子動力模擬,分子嵌合,抗老化,金屬基質蛋白?, | zh_TW |
| dc.subject.keyword | Hyaluronan,Hya-HEAL+,molecular dynamics,molecular docking,anti-aging,matrix metalloproteinase, | en |
| dc.relation.page | 73 | |
| dc.identifier.doi | 10.6342/NTU201803382 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-15 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 土木工程學研究所 | zh_TW |
| 顯示於系所單位： | 土木工程學系 | |
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