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

Autor(es)

Caracelli, Ignez ^[1] ; Vega-Teijido, Mauricio ^[2] ; Zukerman-Schpector, Julio ^[3] ; Cezari, Maria H. S. ^[4] ; Lopes, Jose G. S. ^[5] ; Juliano, Luiz ^[4] ; Santos, Paulo S. ^[6] ; Comasseto, Joao V. ^[6] ; Cunha, Rodrigo L. O. R. ^{[7, 4]} ; Tiekink, Edward R. T. ^[8]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Carlos, BioMat Dept Fis, BR-13565905 Sao Carlos, SP - Brazil

^[2] Univ Estado Sao Paulo UNESP, Fac Ciencias, Dept Fis, Bauru, SP - Brazil

^[3] Univ Fed Sao Carlos, Dept Quim, Lab Cristalog Estereodinam & Modelagem Mol, BR-13565905 Sao Carlos, SP - Brazil

^[4] Univ Fed Sao Paulo, Escola Paulista Med, Dept Biofis, BR-0404420 Sao Paulo - Brazil

^[5] Univ Fed Juiz de Fora, Inst Ciencias Exatas, Dept Quim, Juiz De Fora, MG - Brazil

^[6] Univ Sao Paulo, Inst Quim, Sao Paulo - Brazil

^[7] Univ Fed ABC UFABC, CCNH, Santo Andre, SP - Brazil

^[8] Univ Malaya, Dept Chem, Kuala Lumpur 50603 - Malaysia

• Tipo de documento: Artigo Científico
• Fonte: Journal of Molecular Structure; v. 1013, p. 11-18, APR 11 2012.
• Citações Web of Science: 16

Resumo

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. (AU)

• Processo FAPESP: 06/56078-4 - Estudos estruturais, de docking e de dinâmica molecular aplicados à inibição enzimática de cisteíno proteases por organocalcogênicos
• Beneficiário: Mauricio Angel Vega Teijido
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 07/52734-7 - Estudos estruturais de docking e de dinâmica molecular aplicados à inibição enzimática de cisteíno proteases por organocalcogênios
• Beneficiário: Mauricio Angel Vega Teijido
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores