کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1360559 | 981439 | 2009 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanism of action of N-phenyl-Nâ²-(2-chloroethyl)ureas in the colchicine-binding site at the interface between α- and β-tubulin
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Mechanism of action of N-phenyl-Nâ²-(2-chloroethyl)ureas in the colchicine-binding site at the interface between α- and β-tubulin Mechanism of action of N-phenyl-Nâ²-(2-chloroethyl)ureas in the colchicine-binding site at the interface between α- and β-tubulin](/preview/png/1360559.png)
چکیده انگلیسی
Computational tools such as CoMSIA and CoMFA models reported in a recent study revealed the structure-activity relationships ruling the interactions occurring between hydrophobic N-phenyl-Nâ²-(2-chloroethyl)ureas (CEU) and the colchicine-binding site (C-BS) on βÎÎ-tubulin. Here, we describe the mechanisms involved in the covalent binding of three subsets of CEU derivatives to the C-BS. The FlexiDock experiments confirmed that the interaction of non-covalent portions of the CEU auxophore moiety of CEU is involved in the binding of the drug to the C-BS facilitate the nucleophilic attack of Glu-β198 rather than Cys-β239. In addition, these studies suggest that Cys-β239 together with Asn-α99, Ser-α176, Thr-α177, Leu-β246, Asn-β247, Ala-β248, Lys-β252 and Asn-β256 are implicated in the stabilization of a C-BS-CEU complex prior to the acylation of Glu-β198 by CEU. Our molecular models propose the formation of a stabilized C-BS-CEU complex before the completion of the Glu-β198 acylation; acylation triggering conformational changes of β-tubulin, microtubule depolymerization and anoikis. The computational models presented here might be useful to the design of selective and more potent C-BS inhibitors. Of interest, in vivo acylation of acidic amino acid residues by xenobiotics is an unusual reaction and may open new approaches for the design of irreversible protein inhibitors such as tubulin.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 17, Issue 10, 15 May 2009, Pages 3690-3697
Journal: Bioorganic & Medicinal Chemistry - Volume 17, Issue 10, 15 May 2009, Pages 3690-3697
نویسندگان
Sébastien Fortin, Lianhu Wei, Emmanuel Moreau, Philippe Labrie, Ãric Petitclerc, Lakshmi P. Kotra, René C.-Gaudreault,