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

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

Author Caracelli, Ignez Google Scholar
Vega-Teijido, Mauricio Google Scholar
Zukerman-Schpector, Julio Google Scholar
Cezari, Maria H. S. Autor UNIFESP Google Scholar
Lopes, Jose G. S. Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Santos, Paulo S. Google Scholar
Comasseto, Joao V. Google Scholar
Cunha, Rodrigo L. O. R. Autor UNIFESP Google Scholar
Tiekink, Edward R. T. Google Scholar
Institution Universidade Federal de São Carlos (UFSCar)
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Univ Fed Juiz de Fora
Universidade Federal do ABC (UFABC)
Univ Malaya
Abstract 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 psi-pentagonal bipyramidal based on a C2OCl3(lone pair) donor set. Notable is the presence of an intramolecular axial Te center dot center dot center dot O (carbonyl) interaction, a design element included to reduce hydrolysis. Raman and molecular modelling studies indicate the persistence of the Te center dot center dot center dot O(carbonyl) interaction in the solution (CHCl3) and gasphases, respectively. Docking studies of 3' (i.e. original 3 less one chloride) with Cathepsin B reveals a change in the configuration about the vinyl C = C bond. i.e. to E from Z (crystal structure). This isomerism allows the optimisation of interactions in the complex which features a covalent Te-SGCys29 bond. Crucially, the E configuration observed for 3' allows for the formation of a hypervalent Te center dot center dot center dot O interaction as well as an O center dot center dot center dot H-O 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. (C) 2012 Elsevier B.V. All rights reserved.
Keywords Tellurium
Cathepsin B
X-ray crystal structure
Molecular modelling
Docking
Structure-activity relationships
Language English
Sponsor Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Ministry of Higher Education (Malaysia)
Grant number CAPES: 808/2009
CNPq: 308116/2010-0
CNPq: 306532/2009-3
FAPESP: 06/56078-4
FAPESP: 07/52734-7
Ministry of Higher Education (Malaysia): UM.C/HIR/MOHE/SC/12
Date 2012-04-11
Published in Journal of Molecular Structure. Amsterdam: Elsevier B.V., v. 1013, p. 11-18, 2012.
ISSN 0022-2860 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 11-18
Origin http://dx.doi.org/10.1016/j.molstruc.2012.01.008
Access rights Closed access
Type Article
Web of Science ID WOS:000302666300002
URI http://repositorio.unifesp.br/handle/11600/34797

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