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Metal-mediated binding of benzimidaz...

Kircus, Sandra Roashell.

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Metal-mediated binding of benzimidazole derivatives to serine proteases.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Metal-mediated binding of benzimidazole derivatives to serine proteases./
作者:	Kircus, Sandra Roashell.
面頁冊數:	95 p.
附註:	Adviser: H. Holden Thorp.
Contained By:	Dissertation Abstracts International63-03B.
標題:	Chemistry, Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3047025
ISBN:	0493609989

Metal-mediated binding of benzimidazole derivatives to serine proteases.
Kircus, Sandra Roashell.

Metal-mediated binding of benzimidazole derivatives to serine proteases. - 95 p.

Adviser: H. Holden Thorp.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2002.

The binding of bovine trypsin and bovine thrombin by benzimidazole derivatives mediated by exogenous metal ions was investigated. The binding of BABIM (bis[5-amidino-2-benzmidazolel]methane) and 1RJL118 ([5-amidino-2-benzimidazolyl]-[2-benzimidazolyl]methane) and the synergistic effect in the presence of Zn<super>2+</super>, Cd<super>2+</super>, and Mn<super>2+</super> were measured by inhibition constants (Ki) with respect to the enzymes. BABIM and 1RJL118 are mediocre inhibitors; the Ki of BABIM for trypsin is 2 μM, the Ki of 1RJL118 for trypsin is 0.4 μM, and the Ki of 1RJL118 for thrombin is 87 μM. The metal ions have poor inhibitory qualities (all Ki ≥ 1 mM). However, the presence of Zn<super>2+</super>, Cd<super>2+</super>, or Mn<super>2+</super> with the benzimidazoles greatly enhances their binding affinity.

ISBN: 0493609989Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Metal-mediated binding of benzimidazole derivatives to serine proteases.
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100 1 $a Kircus, Sandra Roashell. $3 1259039
245 1 0 $a Metal-mediated binding of benzimidazole derivatives to serine proteases.
300 $a 95 p.
500 $a Adviser: H. Holden Thorp.
500 $a Source: Dissertation Abstracts International, Volume: 63-03, Section: B, page: 1355.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2002.
520 $a The binding of bovine trypsin and bovine thrombin by benzimidazole derivatives mediated by exogenous metal ions was investigated. The binding of BABIM (bis[5-amidino-2-benzmidazolel]methane) and 1RJL118 ([5-amidino-2-benzimidazolyl]-[2-benzimidazolyl]methane) and the synergistic effect in the presence of Zn<super>2+</super>, Cd<super>2+</super>, and Mn<super>2+</super> were measured by inhibition constants (Ki) with respect to the enzymes. BABIM and 1RJL118 are mediocre inhibitors; the Ki of BABIM for trypsin is 2 μM, the Ki of 1RJL118 for trypsin is 0.4 μM, and the Ki of 1RJL118 for thrombin is 87 μM. The metal ions have poor inhibitory qualities (all Ki ≥ 1 mM). However, the presence of Zn<super>2+</super>, Cd<super>2+</super>, or Mn<super>2+</super> with the benzimidazoles greatly enhances their binding affinity.
520 $a Zn<super>2+</super>-mediated 1RJL118 to trypsin is Ki<super> ′</super> = 50 pM; the same for thrombin is 5 nM. Zn<super>2+</super>-mediated BABIM to trypsin is also 5 nM. Cd<super>2+</super> is a comparatively equal mediator of BABIM to trypsin (Ki<super>′</super> = 10 nM), and Cd<super>2+</super>-mediated 1RJL118 is 62 nM. A modest inhibitor of thrombin is produced by Cd<super>2+</super>-mediated 1RJL118 (Ki = 750 nM). Mn<super>2+</super>-mediated 1RJL118 to trypsin is 31 nM, but is 6 μM for thrombin. Synergy factors for each inhibitor complex were determined to be <1, suggesting cooperativity between the metal ion and benzimidazole.
520 $a The inhibition constants suggest the degree of affinity of these two benzimidazoles for trypsin and thrombin is largely dependent on the metal ion size and metal ion affinity for each ligand. The microenvironment of each serine protease must also be considered.
520 $a Physical characterizations of Zn<super>2+</super>-mediated and Mn<super> 2+</super>-mediated complexes of 1RJL118 to trypsin were performed. Molecular minimization on Zn<super>2+</super>-mediated 1RJL118 to trypsin was performed in AMBER. The 1000-fold increase in affinity going from BABIM to 1RJL118 relies solely on removing the minor destabilizating interaction between the second amidino group on BABIM and Phe41. EPR was used to characterize Mn<super>2+ </super>-mediated 1RJL118 to trypsin. Zn<super>2+</super> and Cd<super>2+ </super> form tetrahedral complexes with the benzimidazoles and the enzyme; Mn<super>2+</super> remains octahedral and bonds with 1RJL118 through the secondary coordination sphere. The inhibitor complex does appear to occupy the active site of the enzyme as do the other inhibitor complexes.
590 $a School code: 0153.
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Chemistry, Inorganic. $3 517253
690 $a 0487
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710 2 0 $a The University of North Carolina at Chapel Hill. $3 1017449
773 0 $t Dissertation Abstracts International $g 63-03B.
790 $a 0153
790 1 0 $a Thorp, H. Holden, $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3047025