A tellurium-based cathepsin B inhibitor: Molecular structure, modelling, molecular docking and biological evaluation

详细信息	查看全文 | 推荐本文 |

• 作者：Ignez Caracelli^a ; ¹ ; ^{ignez@ufscar.br} ; Mauricio Vega-Teijido^b ; ¹ ; ² ; Julio Zukerman-Schpector^c ; Maria H.S. Cezari^d ; José ; G.S. Lopes^e ; Luiz Juliano^d ; Paulo S. Santos^f ; Joã ; o V. Comasseto^f ; Rodrigo L.O.R. Cunha^d ; ^g ; Edward R.T. Tiekink^h
• 关键词：Tellurium ; Cathepsin B ; X-ray crystal structure ; Molecular modelling ; Docking ; Structure&ndash ; activity relationships
• 刊名：Journal of Molecular Structure
• 出版年：2012
• 期刊代码：62_00222860
• 类别：ch
• 出版时间：11 April, 2012
• 卷：1013
• 期：Complete
• 页码：11-18
• 文件大小：930 K

摘要

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 蠄-pentagonal bipyramidal based on a C₂OCl₃(lone pair) donor set. Notable is the presence of an intramolecular axial Te鈰疧(carbonyl) interaction, a design element included to reduce hydrolysis. Raman and molecular modelling studies indicate the persistence of the Te鈰疧(carbonyl) interaction in the solution (CHCl₃) and gas-phases, respectively. Docking studies of 3鈥?/strong> (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鈥?/strong> allows for the formation of a hypervalent Te鈰疧 interaction as well as an O鈰疕O hydrogen bond with the Gly27 and Glu122 residues, respectively. Additional stabilisation is afforded by a combination of interactions spanning the S1, S2, S1鈥?and S2鈥?sub-sites of Cathepsin B. The greater experimental inhibitory activity of 3 compared with analogues is rationalised by the additional interactions formed between 3鈥?/strong> and the His110 and His111 residues in the occluding loop, which serve to hinder the entrance to the active site.