کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1409873 1501801 2012 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A tellurium-based cathepsin B inhibitor: Molecular structure, modelling, molecular docking and biological evaluation
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
A tellurium-based cathepsin B inhibitor: Molecular structure, modelling, molecular docking and biological evaluation
چکیده انگلیسی

The crystallographically determined structure of biologically active 4,4-dichloro-1,3-diphenyl-4-telluraoct-2-en-1-one, 3, shows the coordination geometry for Te to be distorted ψ-pentagonal bipyramidal based on a C2OCl3(lone pair) donor set. Notable is the presence of an intramolecular axial Te⋯O(carbonyl) interaction, a design element included to reduce hydrolysis. Raman and molecular modelling studies indicate the persistence of the Te⋯O(carbonyl) interaction in the solution (CHCl3) and gas-phases, respectively. Docking studies of 3′ (i.e. original 3 less one chloride) with Cathepsin B reveals a change in the configuration about the vinyl CC bond, i.e. to E from Z (crystal structure). This isomerism allows the optimisation of interactions in the complex which features a covalent TeSGCys29 bond. Crucially, the E configuration observed for 3′ allows for the formation of a hypervalent Te⋯O interaction as well as an O⋯HO hydrogen bond with the Gly27 and Glu122 residues, respectively. Additional stabilisation is afforded by a combination of interactions spanning the S1, S2, S1′ and S2′ sub-sites of Cathepsin B. The greater experimental inhibitory activity of 3 compared with analogues is rationalised by the additional interactions formed between 3′ and the His110 and His111 residues in the occluding loop, which serve to hinder the entrance to the active site.


► Tellurium compounds display pharmaceutical potential.
► Cathepsin B is a likely target for thiophilic tellurium.
► Intramolecular Te⋯O(carbonyl) contacts prevent hydrolysis.
► Tellurium forms a Te–S bond with Cathepsin B according to docking studies.
► Optimal ligand⋯Cathepsin B interactions rationalise differences in inhibition.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Structure - Volume 1013, 11 April 2012, Pages 11–18
نویسندگان
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