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The influence of metal ions on the structure of amyloid- β (Aβ) protofibril models was studied through molecular dynamics to explore the molecular mechanisms underlying metal-induced Aβ aggregation relevant in Alzheimer's disease (AD). The models included 36-, 48-, and 188-mers of the Aβ42 sequence and two disease-modifying variants. Primary structural effects were observed at the N-terminal domain, as it became susceptible to the presence of cations. Specially when β-sheets predominate, this motif orients N-terminal acidic residues toward one single face of the β-sheet, resulting in the formation of an acidic region that attracts cations from the media and promotes the folding of the N-terminal region, with implications in amyloid aggregation. The molecular phenotype of the protofibril models based on Aβ variants shows that the AD-causative D7N mutation promotes the formation of N-terminal β-sheets and accumulates more Zn2+, in contrast to the non-amyloidogenic rodent sequence that hinders the β-sheets and is more selective for Na+ over Zn2+ cations. It is proposed that forming an acidic β-sheet domain and accumulating cations is a plausible molecular mechanism connecting the elevated affinity and concentration of metals in Aβ fibrils to their high content of β-sheet structure at the N-terminal sequence. [ABSTRACT FROM AUTHOR]

In the design of 1‐phenylbenzimidazoles as model cyclooxygenase (COX) inhibitors, docking to a series of crystallographic COX structures was performed to evaluate their potential for high‐affinity binding and to reproduce the interaction profile of well‐known COX inhibitors. The effect of ligand‐specific induced fit on the calculations was also studied. To quantitatively compare the pattern of interactions of model compounds to the profile of several cocrystallized COX inhibitors, a geometric parameter, denominated ligand‐receptor contact distance (LRCD), was developed. The interaction profile of several model complexes showed similarity to the profile of COX complexes with inhibitors such as iodosuprofen, iodoindomethacin, diclofenac, and flurbiprofen. Shaping of high‐affinity binding sites upon ligand‐specific induced fit mostly determined both the affinity and the binding mode of the ligands in the docking calculations. The results suggest potential of 1‐phenylbenzimidazole derivatives as COX inhibitors on the basis of their predicted affinity and interaction profile to COX enzymes. The analyses also provided insights into the role of induced fit in COX enzymes. While inhibitors produce different local structural changes at the COX ligand binding site, induced fit allows inhibitors in diverse chemical classes to share characteristic interaction patterns that ensure key contacts to be achieved. Different interaction patterns may also be associated with different inhibitory mechanisms. [ABSTRACT FROM AUTHOR]

A detailed structural analysis of the benzimidazole nitroarenes 1‐(4‐nitrophenyl)‐1H‐1,3‐benzimidazole, C13H9N3O2, (I), 1‐(4‐nitrophenyl)‐2‐phenyl‐1H‐1,3‐benzimidazole, C19H13N3O2, (II), and 2‐(3‐methylphenyl)‐1‐(4‐nitrophenyl)‐1H‐1,3‐benzimidazole, C20H15N3O2, (III), has been performed. They are nonplanar structures whose crystal arrangement is governed by Csp2—H…A (A = NO2, Npy and π) hydrogen bonding. The inherent complexity of the supramolecular arrangements of compounds (I) (Z′ = 2) and (II) (Z′ = 4) into tapes, helices and sheets is the result of the additional participation of π– and n–π* (n = O and Npy; π* = Csp2 and ) interactions that contribute to the stabilization of the equi‐energetic conformations adopted by each of the independent molecules in the asymmetric unit. In contrast, compound (III) (Z′ = 1) is self‐paired, probably due to the effect of the steric demand of the methyl group on the crystal packing. Theoretical ab initio calculations confirmed that the presence of the arene ring at the benzimidazole 2‐position increases the rotational barrier of the nitrobenzene ring and also supports the electrostatic nature of the orthogonal ONO…Csp2 and Npy…NO2 interactions. [ABSTRACT FROM AUTHOR]

Intramolecular hydrogen bond (HB) formation was analyzed in the model compounds N-(2-benzoylphenyl)acetamide, N-(2-benzoylphenyl)oxalamate and N1,N2-bis(2-benzoylphenyl)oxalamide. The formation of three-center hydrogen bonds in oxalyl derivatives was demonstrated in the solid state by the X-ray diffraction analysis of the geometric parameters associated with the molecular structures. The solvent effect on the chemical shift of H6 [δH6(DMSO-d6)–δH6(CDCl3)] and Δδ(ΝΗ)/ΔT measurements, in DMSO-d6 as solvent, have been used to establish the energetics associated with intramolecular hydrogen bonding. Two center intramolecular HB is not allowed in N-(2-benzoylphenyl)acetamide either in the solid state or in DMSO-d6 solution because of the unfavorable steric effects of the o-benzoyl group. The estimated ΔH° and ΔS° values for the hydrogen bonding disruption by DMSO-d6 of 28.3(0.1) kJ·mol-1 and 69.1(0.4) J·mol-1·K-1 for oxalamide, are in agreement with intramolecular three-center hydrogen bonding in solution. In the solid, the benzoyl group contributes to develop 1-D and 2-D crystal networks, through C–H•••A (A = O, π) and dipolar C=O•••A (A = CO, π) interactions, in oxalyl derivatives. To the best of our knowledge, this is the first example where three-center hydrogen bond is claimed to overcome steric constraints. [ABSTRACT FROM AUTHOR]

In this work, a series of amides has been studied as hydrogen bonding stabilising species of the reduction intermediates of a weakly basic quinone such as chloranil. The amide structure was selected in order to evaluate the role of a single or three centered intramolecular hydrogen bond on the intermolecular hydrogen bonding interaction with the quinone reduction products. The association process between the semiquinone and the amides is not important. However, the dianion is associated according to different thermodynamic and kinetic conditions. The voltammetric behaviour of these systems was studied by simulation of two consecutive electron transfer steps with two successive association processes coupled to the dianion. The first association process presents a wide range of equilibrium constant values. According to the amide structure, the interference of the electron transfer kinetics on the association processes, was established to be increased with the extent of the interaction, which is explained by considering the acidity of the hydrogen donor groups in the amide and the participation of two intermolecular hydrogen bonds. [Copyright &y& Elsevier]

• Interaction between α-zein and Ca2+ in nixtamalization was analyzed and described. • The calcium-binding constant of α-zein from nixtamalized flour was 1.45/mM. • α-Zein from nixtamalized flour presented a higher affinity for Ca2+. • Calcium bridges occurs mainly through carboxylate from C-ter of zein. The possible interactions between α-zein and Ca2+ in nixtamalization process were analyzed from a multidisciplinary approach, considering the effect of these interactions on the thermal properties of the nixtamalized flour. SDS-PAGE under reducing and non-reducing conditions did not reveal differences between patterns of zeins from nixtamalized and control samples. However, analysis from affinity capillary electrophoresis indicated an increment in protein volume when calcium is added to zein extracted from nixtamalized flour. In addition, the binding constant for the zein-calcium interaction was calculated indicating a higher affinity for calcium by zein from nixtamalized samples. Molecular dynamics simulations indicated that the interaction α-zein-Ca2+ through C-ter was more favorable than Glu48. However, in excess of Ca2+ ions, each site could bind one calcium atom at the same time, confirming that aggregation of α-zein through calcium bridges is possible, expanding the technological applications of this protein. [ABSTRACT FROM AUTHOR]

Discusses the crystal structure of ethyl N-phenyloxamate. Intramolecular hydrogen-bonding interactions; Supramolecular arrangement of the compound; Hydrogen-bonding geometry.

Context: Several descriptors from conceptual density functional theory (cDFT) and the quantum theory of atoms in molecules (QTAIM) were utilized in Random Forest (RF), LASSO, Ridge, Elastic Net (EN), and Support Vector Machines (SVM) methods to predict the toxicity (LD50) of sixty-two organothiophosphate compounds. The A-RF-G1 and A-RF-G2 models were obtained using the RF method, yielding statistically significant parameters with good performance, as indicated by R2 values for the training set (R2Train) and R2 values for the test set (R2Test), around 0.90. Methods: The molecular structure of all organothiophosphates was optimized via the range-separated hybrid functional ωB97XD with the 6–311 + + G** basis set. Seven hundred and eighty-seven descriptors have been processed using a variety of machine learning algorithms: RF LASSO, Ridge, EN and SVM to generate a predictive model. The properties were obtained with Multiwfn, AIMALL and VMD programs. Docking simulations were performed by using AutoDock 4.2 and LigPlot + programs. All the calculations in this work are carried out in Gaussian 16 program package. [ABSTRACT FROM AUTHOR]

Compounds containing carbamate moieties and their derivatives can generate serious public health threats and environmental problems due their high potential toxicity. In this study, a quantitative structure–toxicity relationship (QSTR) model has been developed by using one hundred seventy-eight carbamate derivatives whose toxicities in rats (oral administration) have been evaluated. The QSRT model was rigorously validated by using either tested or untested compounds falling within the applicability domain of the model. A structure-based evaluation by docking from a series of carbamates with acetylcholinesterase (AChE) was carried out. The toxicity of carbamates was predicted using physicochemical, structural, and quantum molecular descriptors employing a DFT approach. A statistical treatment was developed; the QSRT model showed a determination coefficient (R2) and a leave-one-out coefficient (Q2LOO) of 0.6584 and 0.6289, respectively. [ABSTRACT FROM AUTHOR]

Since the high incidence of aflatoxin M1 (AFM1) in milk and dairy products poses a serious risk to human health, this work aimed to investigate the complex formation between bovine α-lactalbumin (α-La) and AFM1 using different spectroscopic methods coupled with molecular docking studies. Fluorescence spectroscopy measurements demonstrated the AFM1 addition considerably reduced the α-La fluorescence intensity through a static quenching mechanism. The results indicated on the endothermic character of the reaction, and the hydrophobic interaction played a major role in the binding between AFM1 and α-La. The binding site stoichiometric value (n = 1.32) and a binding constant of 2.12 × 103 M−1 were calculated according to the Stern-Volmer equation. The thermodynamic parameters ΔH , ΔS and ΔG b were determined at 93.58 kJ mol−1, 0.378 kJ mol−1 K−1 and -19.17 ± 0.96 kJ mol−1, respectively. In addition, far-UV circular dichroism studies revealed alterations in the α-La secondary structures when the α-La-AFM1 complex was formed. An increased content of the α-helix structures (from 35 to 40%) and the β-sheets (from 16 to 19%) were observed. Furthermore, protein-ligand docking modelling demonstrated AFM1 could bind to the hydrophobic regions of α-La protein. Overall, the gathered results confirmed the α-La-AFM1 complex formation. Unlabelled Image • Interaction of AFM1 and α-La was studied by in vitro and in silico methods. • The formation of a complex between AFM1 and α-La by spectroscopy methods was demonstrated. • Thermodynamics parameters demonstrated that the interaction is hydrophobic. • The interaction of AFM1 with α-La causes ordering of its secondary structures. • Two possible binding sites for AFM1 on α-La was founded by molecular docking. [ABSTRACT FROM AUTHOR]

Being the base of several non-communicable diseases, including cancer, inflammation is a complex process generated by tissue damage or change in the body homeostatic state. Currently, the therapeutic treatment for chronic inflammation related diseases is based on the use of selective cyclooxygenase II enzyme, COX-2, inhibitors or Coxibs, which have recently regained attention giving their preventive role in colon cancer. Thus, the discovery of new molecules that selectively inhibit COX-2 and other inflammatory mediators is a current challenge in the medicinal chemistry field. 1-Phenylbenzimidazoles have shown potential COX inhibitory activity, because they can reproduce the interaction profile of known COX inhibitors. Therefore, in the present investigation a series of 1,2-diphenylbenzimidazoles (DPBI) with different aromatic substitutions in the para position were synthesized and their interaction with COX-2 and nitric oxide synthase, iNOS, was determined in silico, in vitro and in vivo. Compound 2-(4-bromophenyl)-1-(4-nitrophenyl)-1 H -benzo[ d ]imidazole showed the best inhibition towards COX-2, while compounds N -(4-(2-(4-bromophenyl)-1 H -benzo[ d ]imidazol-1-yl)phenyl)acetamide and N -(4-(2-(4-chlorophenyl)-1 H -benzo[ d ]imidazol-1-yl)phenyl)acetamide diminished the production of NO in vitro. Additionally, they had a significant anti-inflammatory activity in vivo when given orally. [ABSTRACT FROM AUTHOR]

The cellular prion protein (PrPC) has emerged as an important copper binding protein. The interaction of copper with PrPC may play important roles in both the physiological function of the protein, and in the pathogenesis of prion diseases. The copper coordination chemistry of PrPC is complex, as different Cu(II) coordination modes can be formed depending on pH and copper to protein ratios, and involving six different His residues in the N-terminal region of the protein. The nature of these Cu(II) binding sites has been studied using theoretical tools, which expand on the information obtained from experimental results and provide important insights into Cu–PrPC interactions. This article provides a general overview of the different Cu(II) binding sites in PrPC and their redox properties, highlighting the contributions from electronic structure calculations and molecular dynamics simulations. Particular emphasis is placed in discussing the electronic structure of each Cu binding mode, as it is intimately related to redox properties. For most Cu binding modes, the dominating Cu(II) bonding interactions involve deprotonated amide nitrogens, which yield Cu一Namide bonds that are significantly more covalent than the Cu一NHis bond. The key factors that determine the direction of Cu(II) binding to backbone amides in the vicinity of the anchoring His are discussed. Additionally, the impact of Cu–PrPC interactions in protein folding and in the potential initiation of PrPC aggregation is discussed. [Copyright &y& Elsevier]