RESUMO

The influence of metal ions on the structure of amyloid- ß (Aß) protofibril models was studied through molecular dynamics to explore the molecular mechanisms underlying metal-induced Aß aggregation relevant in Alzheimer's disease (AD). The models included 36-, 48-, and 188-mers of the Aß42 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 ß-sheets predominate, this motif orients N-terminal acidic residues toward one single face of the ß-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 Aß variants shows that the AD-causative D7N mutation promotes the formation of N-terminal ß-sheets and accumulates more Zn2+, in contrast to the non-amyloidogenic rodent sequence that hinders the ß-sheets and is more selective for Na+ over Zn2+ cations. It is proposed that forming an acidic ß-sheet domain and accumulating cations is a plausible molecular mechanism connecting the elevated affinity and concentration of metals in Aß fibrils to their high content of ß-sheet structure at the N-terminal sequence.

Assuntos

Peptídeos beta-Amiloides , Simulação de Dinâmica Molecular , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/genética , Conformação Proteica em Folha beta , Humanos , Zinco/metabolismo , Zinco/química , Doença de Alzheimer/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/genética , Metais/metabolismo , Metais/química

RESUMO

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.

Assuntos

Acetilcolinesterase , Carbamatos , Acetilcolinesterase/metabolismo , Animais , Carbamatos/química , Carbamatos/toxicidade , Relação Quantitativa Estrutura-Atividade , Ratos

RESUMO

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 ΔGb were determined at 93.58 kJ mol-1, 0.378 kJ mol-1 K-1 and -19.17 ±â€¯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 ß-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.

Assuntos

Aflatoxina M1/química , Contaminação de Alimentos/análise , Lactalbumina/química , Animais , Sítios de Ligação , Bovinos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Leite/química , Simulação de Acoplamento Molecular , Estrutura Secundária de Proteína , Soroalbumina Bovina/química , Termodinâmica

RESUMO

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)-1H-benzo[d]imidazole showed the best inhibition towards COX-2, while compounds N-(4-(2-(4-bromophenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide and N-(4-(2-(4-chlorophenyl)-1H-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.

Assuntos

Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Benzimidazóis/síntese química , Benzimidazóis/química , Bovinos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Inflamação/tratamento farmacológico , Masculino , Estrutura Molecular , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade

RESUMO

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.

Assuntos

Benzimidazóis/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Cristalografia por Raios X , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Bases de Dados de Proteínas , Indometacina/química , Indometacina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Prostaglandina-Endoperóxido Sintases/química , Termodinâmica

RESUMO

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.

Assuntos

Cálcio/química , Modelos Teóricos , Zeína/química , Sítios de Ligação , Cálcio/metabolismo , Culinária , Eletroforese em Gel de Poliacrilamida , Farinha/análise , Simulação de Dinâmica Molecular , Termodinâmica , Temperatura de Transição , Zea mays/metabolismo , Zeína/metabolismo

RESUMO

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-πNO2 and n-π* (n = O and Npy; π* = Csp2 and NNO2) 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.

RESUMO

Structural and electronic properties of a series of 25 phosphonate derivatives were analyzed applying density functional theory, with the exchange-correlation functional PBEPBE in combination with the 6-311++G** basis set for all atoms. The chemical reactivity of these derivatives has been interpreted using quantum descriptors such as frontier molecular orbitals (HOMO, LUMO), Hirshfeld charges, molecular electrostatic potential, and the dual descriptor [[Formula: see text]]. These descriptors are directly related to experimental median lethal dose ([Formula: see text], expressed as its decimal logarithm [[Formula: see text]([Formula: see text]] through a multiple linear regression equation. The proposed model predicts the toxicity of phosphonates in function of the volume (V), the load of the most electronegative atom of the molecule (q), and the eigenvalue of the molecular orbital HOMO ([Formula: see text]. The obtained values in the internal validation of the model are: [Formula: see text]%, [Formula: see text]%, [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]%. The toxicity of nine phosphonate derivatives used as test molecules was adequately predicted by the model. The theoretical results indicate that the oxygen atom of the O=P group plays an important role in the interaction mechanism between the phosphonate and the acetylcholinesterase enzyme, inhibiting the removal of the proton of the ser-200 residue by the his-440 residue.

Assuntos

Simulação por Computador , Organofosfonatos/química , Organofosfonatos/toxicidade , Relação Quantitativa Estrutura-Atividade , Elétrons , Dose Letal Mediana , Modelos Moleculares , Conformação Molecular

RESUMO

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 ΔHº and ΔSº 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.

Assuntos

Hidrogênio/química , Fenilalanina/química , Soluções/química , Cristalografia por Raios X , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fenilalanina/análogos & derivados , Solventes/química , Termodinâmica , Difração de Raios X

RESUMO

The oxamate group in the title compound, C(10)H(11)NO(3), is almost coplanar with the phenyl ring because of intramolecular hydrogen-bonding interactions, and the structure can be described as an anilide single bonded to an ethyl carboxylate group. The supramolecular structure is achieved through intermolecular hard N-H...O and soft C-H...X (X = O and phenyl) hydrogen-bonding interactions.