Study of the chelating properties of Ge(OH)(2) functionality as metal binding group for Zn2+ cation in simplified protease-like environments: a DFT analysis

作者：Rodriguez Ortega Pilar Gema; Montejo Manuel; Lopez Gonzalez Juan Jesus

来源：Journal of Molecular Modeling, 2014, 20(9): 2430.

DOI：10.1007/s00894-014-2430-2

• Active site model
• AIM
• Binding energy
• DFT
• Gem-germanediol
• NBO
• Zinc binding group (ZBG)

The development of protease%26apos;s inhibitors is an active field of research in the pharmaceutical industry. As concerns the design of new inhibitors, the theoretical study of the binding patterns and energies of known metal binding groups (MBGs) toward Zn2+ using quantum-chemical calculations may offer a better understanding of their interaction models and may be useful for the improvement and design of novel ZBGs. Here the properties of gem-Ge(OH)(2)-based compounds as ZBG were assessed theoretically using DFT calculations. [Zn(Imdz)(2)R-OH2](2+) complexes (Imdz = imidazole rings; R = imidazole ring, acetic acid molecule or acetate anion) were used to partially reproduce the coordination sphere in metalloproteases (ACE, amgiotensin converting enzyme, and TLN, thermolysine) being inhibited by related compounds (i.e., silanediols). TheMBG-Zn2+ interaction was analyzed through the energy of the reaction: [Zn(Imdz)(2)R-OH2](2+) + L -%26gt; [Zn(Imdz)(2)R-L](2+) + H2O using DFT (M06L/cc-pVDZ) in gas-phase and in solution (IEF-PCM). Although the functional used (M06L) has proven its efficiency to study systems containing transition metal governed by non-covalent interactions, dispersion effects were implemented by the correction of the computed energies using the DFT-D3 program. Accounting for dispersion effects produced a systematic increase of c.a. 13 kJ mol(-1) on the energies, whereas the effect of solvent goes in the opposite direction (i.e., BE under the IEF-PCM model are on average 125 kJ mol(-1) lower). The Ge(OH)(2)-Zn2+ interaction seems to be similar (or even stronger) than the Si(OH)(2)-Zn2+. Their better performance as ZBG is explained by the combined NBO-AIM analysis. The results of this work may encourage the preparation, isolation, and experimental assay of the chelating properties of these compounds, which may propose a new family of protease%26apos;s inhibitors.

• 出版日期2014-9