SCHEDULED MAINTENANCE
Insight into inhibition of the human amyloid beta protein precursor (APP: PDB ID 3UMI) using (E)-N-(pyridin-2-ylmethylene)arylamine (LR) models: structure elucidation of a family of ZnX2-LR complexes†
Abstract
The amyloid beta precursor protein (APP) and its neurotoxic cleavage product amyloid beta (Aβ) are a cause of Alzheimer's disease and appear essential for neuronal development and cell homeostasis. Proteolytic processing of APP is influenced by metal ions and protein ligands, however the structural and functional mechanism of APP regulation is not known so far. In this context, molecular modeling studies were performed to understand the molecular behavior of (E)-N-(pyridin-2-ylmethylene)arylamines (LR) with an E2 domain of the APP in its complex with zinc (APP; PDB ID: 3UMI). Docking results indeed confirmed that the LR interacts with Zn in the binding site of the protein between two α-helical chains. In view of these findings, LR was further investigated for complexation reactions with Zn2+ in order to establish the structural models in solution and in the solid state. Five new Zn2+ complexes of compositions viz. [Zn(Br)2(L2-Me)] (1), [Zn(Br)2(L2-OMe)] (2), [Zn(I)2(L2-OMe)] (3), [Zn(NO3)2(L2-OMe)(H2O)] (4) and [Zn(L4-Me)2(H2O)2](NO3)2 (5) were synthesized and their structures were ascertained by microanalysis, IR and 1H NMR spectroscopy, and single-crystal X-ray diffraction. The zinc atom in complex 1 exhibits a distorted tetrahedral geometry while the crystal structures of complexes 2 and 3 show distorted square pyramidal geometries. The zinc cation in 4 and 5 has an octahedral coordination environment, but in 5 the zinc coordination geometry is less distorted. The Zn(II) cations take part in one (1 and 5) or two (2–4) 5-membered metallacycles imposed by the NN or NNO chelation modes of LR. The significant intermolecular π⋯π interactions are also discussed.
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