Spectroscopic study and application of the interaction mechanism of meloxicam with trypsin

Abstract

In order to explore the interaction between meloxicam and trypsin, the interaction mechanism between meloxicam and trypsin was studied by fluorescence spectrum, UV-vis absorption spectrum, circular dichroism spectrum, and molecular docking simulation under the experimental condition of pH = 7.40. The results of spectral experiments showed that meloxicam could effectively quench the internal fluorescence of trypsin in the form of static quenching, formed a stable complex at 1:1, and changed the conformation of trypsin. The results of thermodynamic constant showed that ΔG?H?S?>?0 indicates that the main force type of the binding system was hydrophobic interaction and hydrogen bonding. Molecular docking technique showed that the best binding site between meloxicam and trypsin was near the catalytic active center of trypsin, and the interaction between them changed the microenvironment of amino acid residues in the catalytic active center of trypsin. The mathematical model of drug and protein showed that when the concentration ratio of meloxicam to trypsin was 1:1, the protein binding rate of the binding system was 5.15%. The concentration ratio of meloxicam to trypsin was 30: 1, and the protein binding rate was 45.4%. The results showed that when the drug concentration was high, the binding effect of the system had a great influence on the concentration of free trypsin.     

Organocatalysis: quantum chemical modeling of nucleophilic addition to α,β‐unsaturated carbonyl compounds

One of the successful transformations within the field of organocatalysis, the organocatalytic asymmetric addition of nitromethane to α,β‐unsaturated aldehydes and ketones, has been studied by quantum chemical modeling. The level of accuracy of the hybrid density functional theory method B3LYP/6‐31G(d) was compared to a high level ab initio benchmark for this reaction. It is concluded that B3LYP/6‐31G(d) performs very well for this reaction type, giving good estimates of critical energies. The reaction between acrolein and nitromethane was studied in detail. The reaction mechanism revealed an intermediate oxazolidin structure, which is currently unknown. Alkyl substitution in various positions on the amine catalyst or α,β‐unsaturated carbonyl compound influences the reactivity in a predictive fashion. The iminium ion, prop‐2‐en‐iminium, is less activated towards nucleophilic attack compared to protonated acrolein. Copyright © 2007 John Wiley & Sons, Ltd.     

A new method for functionalizing α,γ‐dinitro compounds at the β‐position: application to the cyclization of β‐alkoxy‐α,γ‐dinitro compounds

Treatment of 2,4‐dinitropentane with bromine and sodium methoxide in methanol, affords formation of an ether product, 2,4‐dibromo‐3‐methoxy‐2,4‐dinitropentane, in 59% yield as a mixture of three diastereomers. This observation has led to a general synthesis of 3‐alkoxy‐2,4‐dibromo‐2,4‐dinitropentanes, obtained in 75‐86% yield from 2,4‐dibromo‐2,4‐dinitropentane as the preferred reactant. 4‐Bromo‐2,4‐dinitro‐2‐pentene has been identified as an intermediate in these reactions. The nitroalkene has been isolated and undergoes conjugate addition with alkoxides to afford the same ether products after brominative work‐up. The nitroalkene undergoes conjugate addition with sodium azide to give 3‐azido‐2,4‐dibromo‐2,4‐dinitropentane in 38% yield as a mixture of two isomers in which the (R*,R*) isomer predominates. Sequential treatment of 2,4‐dibromo‐2,4‐dinitropentane with sodium methoxide followed by sodium iodide and acetic acid gives 3‐methoxy‐2,4‐dinitropentane in 63% yield, the overall product of simple methoxylation of 2,4‐dinitropentane. However, attempted complete debromination of 2,4‐dibromo‐3‐methoxy‐2,4‐dinitropentane with excess sodium iodide and acetic acid results only in monodebromination to give 2‐bromo‐3‐methoxy‐2,4‐dinitropentane in 86% yield. Likewise, 2‐bromo‐3‐ethoxy‐2,4‐dinitropentane is formed in 93% yield from the ethoxy analog. A mechanistic rationale is offered for condition‐specific removal of the second Br atom in these reactions. Treatment of 3‐methoxy‐2,4‐dinitropentane with potassium acetate/iodine in dimethyl sulfoxide affords formation of 4,5‐dihydro‐3,4‐dimethyl‐3‐methoxy‐4‐nitroisoxazole 2‐oxide in 30% yield as a single diastereomer. Conversion of 2‐bromo‐3‐methoxy‐2,4‐dinitropentane in 15% yield to 4,5‐dihydro‐3,4‐dimethyl‐3‐methoxy‐4‐nitroisoxazole 2‐oxide is also possible by using potassium acetate in dimethyl sulfoxide. The mechanistic pathways for formation of 4,5‐dihydro‐3,4‐dimethyl‐3‐methoxy‐4‐nitroisoxazole 2‐oxide apparently involve unstable 3‐methoxy‐1,2‐dimethyl‐1,2‐dinitrocyclopropane as the common intermediate. Similarly, 2‐bromo‐3‐ethoxy‐2,4‐dinitropentane affords 4,5‐dihydro‐3‐ethoxy‐3,4‐dimethyl‐4‐nitroisoxazole 2‐oxide in 13% yield. Copyright © 2013 John Wiley & Sons, Ltd.     

Spectroscopic and structural investigations of α‐, β‐, and γ‐AlH3 phases

With its reputation as a high‐energy density fuel, aluminum hydride (AlH₃) has received renewed attention as a material that is particularly suitable, not only for hydrogen storage but also for rocket propulsion. While the various phases of AlH₃ have been investigated theoretically, there is a shortage of experimental studies corroborating the theoretical findings. In response to this, we present here an investigation of these compounds based primarily on two research areas in which there is the greatest scarcity of information in the literature, namely Raman and infrared (IR) absorption analysis. To the authors' knowledge, this is the first report of experimental far‐IR absorption results on these compounds. Two different samples prepared by broadly similar ethereal reactions of AlCl₃ with LiAlH₄ were analyzed. Both Raman and IR absorption measurements indicate that one sample is purely γ‐AlH₃ and that the other is a mixture of α‐, β‐, and γ‐AlH₃ phases. X‐ray diffraction confirms the spectroscopic findings, most notably for the β‐AlH₃ phase, for which optical spectroscopic data are reported here for the first time. Copyright © 2010 John Wiley & Sons, Ltd.     

In-Silico Study on the Interaction of Saffron Ligands and Beta-Lactoglobulin by Molecular Dynamics and Molecular Docking Approach

Safranal, crocetin, and dimethylcrocetin are secondary metabolites found in saffron and have a wide range of biological activities. An investigation of their interaction with a transport protein, such as β-lactoglobulin (β-lg), at the atomic level could be a valuable factor in controlling their transport to biological sites. The interaction of these ligands and β-lg as a transport protein was investigated using molecular docking and molecular dynamics (MD) simulation methods. The molecular docking results showed that safranal and crocetin bind on the surface of β-lg. However, dimethylcrocetin binds in the internal cavity of β-lg. The β-lg affinity for binding saffron ligands decreases in the following order: crocetin > dimethylcrocetin > safranal. The analysis of MD simulation trajectories showed that the β-lg and β-lg–ligand complexes became stable at approximately 3000 ps and that there was little conformational change in the β-lg–safranal and β-lg–dimethylcrocetin complexes over a 10-ns timescale. In addition, the profiles of atomic fluctuations showed the rigidity of the ligand binding site during the simulation time.     

Synthesis of novel bis(β‐cyclodextrin)s linked with aromatic diamine and their molecular recognition with model substrates

Novel β‐cyclodextrin (β‐CD) dimers with aromatic diamine linkers, 1,3‐(aminomethyl)‐benzylamine‐bridged bis(6‐amino‐6‐deoxy‐β‐CD) (2) , 4,4′‐diaminodiphenylmethano‐bridged bis(6‐amino‐6‐deoxy‐β‐CD) (3) , and 4,4′‐ ethylenedianiline‐bridged bis(6‐amino‐6‐deoxy‐β‐CD) (4) , were synthesized. The inclusion complexation behaviors of these compounds, together with 4,4′‐aminophenyl ethyl‐bridged bis(6‐amino‐6‐deoxy‐β‐CD) (5) , with substrates such as acridine red (AR), neutral red (NR), ammonium 8‐anilino‐1‐naphthalenesulfonate (ANS), sodium 2‐(p‐toluidinyl) naphthalenesulfonate (TNS), rhodamine B (RhB), and brilliant green (BG), were investigated by ultraviolet, fluorescence, circular dichroism, and 2D NMR spectroscopy. The results indicated that the two linked CD units cooperatively bound to a guest, and the molecular binding affinity toward substrates, especially curved guest ANS and linear guests such as NR and AR, was increased. The linker length between two CD units played a crucial role in the molecular recognition of the hosts with guest dyes. The binding constants of the hosts for AR, TNS, ANS, and RhB decreased with increasing linker length in hosts 2‐4 . Moreover, structurally similar hosts 3 and 5 exhibited very different binding behavior for the guests. Host 5 showed much higher Ks values toward positively charged guests and lower Ks toward negatively charged guests than host 3 . The 2D NMR spectra of hosts 3 and 5 with RhB were acquired to understand the binding difference between 3 and 5 . The molecular binding ability and selectivity of model substrates by these hosts were sufficiently investigated to reveal not only the cooperative contributions of the linker group and CD cavities upon inclusion complexation with dye guest molecules, but also the controlling factors for the molecular selective binding. Copyright © 2008 John Wiley & Sons, Ltd.     

Gas‐phase elimination kinetics of selected aliphatic α,β‐unsaturated aldehydes catalyzed by hydrogen chloride

The gas‐phase elimination of 2‐methyl‐2‐propenal catalyzed by HCl yields propene and CO gas, while E‐2‐pentenal with the same catalyst gives butene and CO gas. The kinetics determinations were carried out in a static system with the reaction vessels deactivated with allyl bromide and the presence of the free radical inhibitor toluene. Temperature and pressure ranges were 350.0–410.0 °C and 34–76 Torr. The elimination reactions are homogeneous and unimolecular, and follow a first‐order rate law. The rate coefficients for the reactions are expressible by the following Arrhenius equations: Data from the kinetic and thermodynamic parameters of these catalyzed elimination reactions implies a mechanism of a concerted five‐membered cyclic transition state structure for the formation of the corresponding olefin and carbon monoxide. Copyright © 2015 John Wiley & Sons, Ltd.     

Complexation of niflumic acid with native and hydroxypropylated α‐ and β‐cyclodextrins in aqueous solution

Interactions between niflumic acid and native and hydroxypropylated α‐ and β‐cyclodextrins (CDs) were investigated by ¹H NMR, UV‐vis spectroscopy, densimetry, and calorimetry at pH = 7.4 (phosphate buffer) and T = 298.15 K. Thermodynamic parameters of 1:1 complex formation were calculated and discussed in terms of influence of cavity size and availability of hydroxypropyl substituents on the complex stability. The ¹H NMR data indicated the inclusion of niflumic acid into macrocyclic cavity of all CDs under study. It was found that both phenyl and pyridine rings of niflumic acid molecule can be included in the cyclodextrin cavity. The co‐existence of two different kinds of 1:1 inclusion complexes in the solution was suggested. In spite of the fact that binding of niflumic acid with α‐cyclodextrin is more enthalpically favorable, stability of the inclusion complexes is very low due to the enthalpy–entropy compensation effect. Complex formation of β‐CDs with niflumic acid is characterized by the higher enthalpy and entropy changes caused by more intense dehydration. Introduction of hydroxypropyl groups in the cyclodextrin molecule was found to promote the binding with niflumic acid. Copyright © 2008 John Wiley & Sons, Ltd.     

Uniaxial magnetic anisotropy in epitaxial α‐Fe() films

The magnetic anisotropy of epitaxial, high‐index Fe() films is investigated. The strength of the in‐plane uniaxial magnetic anisotropy increases monotonically with the inclination angle φ between Fe(001) and Fe(). This increase is demonstrated to be caused by the cubic magnetocrystalline anisotropy and not by surface‐ or interface‐related effects.     

Kinetic and mechanism of the homogeneous,unimolecular elimination of α,β‐unsaturated aldehydes in the gas phase

The gas phase thermal decarbonylation of α,β‐unsaturated aldehydes E‐2‐butenal and E‐3‐phenyl‐2‐methylpropenal was studied in a static system over the temperature range 380.5–490.0 °C and pressure range 55.5–150 Torr. The reactions are homogeneous and unimolecular and obey a first‐order rate law. The rate coefficient is represented by the following Arrhenius equations: The elimination products of 2‐butenal are propene and CO gas, while 3‐phenyl‐2‐methylpropenal produces α‐methylstyrene, cis‐trans‐β‐methylstyrene, indan, and CO gas. Kinetic and thermodynamic parameters suggest these elimination reactions to proceed through a three‐membered cyclic transition state type of mechanisms. However, a two steps mechanisms for the formation of a carbene type of intermediate through a four‐membered cyclic transition structure can not be overlooked. Copyright © 2007 John Wiley & Sons, Ltd.     

Computational study of the proton affinity and basicity of structurally diverse α1‐adrenoceptor ligands

The α₁‐adrenoceptor is a target for the treatment of several conditions from hypertension to benign prostatic hyperplasia. In this paper, we describe a new analysis approach to explore the conformational space of several ligands of the α₁‐adrenoceptor and we also present the calculation of their proton affinity and basicity. For each compound a conformational search followed by a semi‐empirical optimisation was performed and a selection of conformations for each ligand was subjected to further optimisation using density functional theory methods. Different positions were explored to determine the favoured site of protonation, and then, the proton affinity (in the gas phase) and basicity (using the polarisable continuum model for the aqueous solution) were calculated for each of them. In addition, an alternative method using one explicit water molecule in combination with the polarisable continuum model for aqueous solvent was explored. Moreover, the acid dissociation constant (pK_a) in water of these 26 compounds was calculated because this is an important parameter for a ligand when binding to its receptor. The experimental pK_a values of six of these ligands and those of two compounds with a very low and a very large pK_a were used to validate the theoretical methodology. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of an α‐amino nitrile and a bis α‐amino nitrile derivative of thiadiazole: reaction mechanism

The first nucleophilic addition of an inorganic nucleophile (cyanide) to the activated, rigid, α‐diazomethine groups of a 1,2,5‐thiadiazole 1,1‐dioxide is reported here. An α‐amino nitrile and a bis α‐amino nitrile derivatives were obtained in good yields (62 and 98%, respectively) and characterized by spectroscopic, analytical, and single crystal X‐ray diffraction techniques. The course of the reaction, followed by cyclic voltammetry (CV), showed that cyanide adds to only one of the two C?N double bonds of the thiadiazole, forming an anion from which an N‐methyl derivative was obtained. Adequate concentrations of cyanide and methyl iodide (MeI) produced directly the bis α‐amino nitrile derivative. Copyright © 2007 John Wiley & Sons, Ltd.     

Density functional study of α–β phase transition of polyvinylidene difluoride

We perform density functional calculations to investigate structural and dynamical properties of crystalline polyvinylidene difluoride (PVDF) associated with the transition from α to β phase. We examine the change of the conformational energy and the corresponding structure of each phase depending on the lattice parameters of the orthorhombic crystalline structure. From this information, we construct the path that connects the point where the α phase is most stable to the point where the β phase is most stable, and identify the sub‐ region in the lattice parameter space where α and β phases have the same energy. In this sub‐region, we locate the point which gives the lowest conformation energy for both α and β phases, and examine the behaviour of the lowest energy profile and corresponding change of intermediate structures as the conformation of the PVDF chain transforms from α phase to β phase. Finally we perform ab‐initio molecular dynamics simulations and analyse the characteristic dynamics associated with transition from α to β phase. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Solid-state synthesis of potassium β- and β″-gallates

Direct synthesis of K-β- and β″-gallates by Ga₂O₃–K₂O solid-state reaction is described. The formation of K-β- or β″-gallates depends on the initial Ga₂O₃ phase. -Ga₂O₃ leads to K-β-gallate; β-Ga₂O₃ leads to K-β″-gallate. K-β″-Gallate is stable <1200°C. The high temperature stability of K-β″-gallate can be enhanced by doping with aliovalent ions.     

Semiempirical QSAR study and ligand receptor interaction of estrogens

Softness values E_n of estrogen derivatives and softness values E_m of receptor lysine, histidine, tyrosine and cysteine have been evaluated by Klopman equation. The required parameters for the solution of Klopman equation have been calculated with the help of PM3 method. The difference E_nm between E_n and E_m has been derived for QSAR study. The estrogen derivatives have been divided into four different sets on the basis of their structural similarities, and their biological activity taken from literature in terms of relative binding affinity (RBA). The QSAR study shows that, E_nm values provide good relationship with biological activity.     

Raman spectroscopy and characterisation of α‐gallium oxyhydroxide and β‐gallium oxide nanorods

Raman spectroscopy complemented by infrared spectroscopy was used to characterise both gallium oxyhydroxide (α‐GaO(OH)) and gallium oxide (β‐Ga₂O₃) nanorods synthesised with and without the surfactants using a soft chemical methodology at low temperatures. Nano‐ to micro‐sized gallium oxyhydroxide and gallium oxide materials were characterised and analysed by both X‐ray diffraction and Raman spectroscopy. Rod‐like GaO(OH) crystals with average length of ∼2.5 µm and width of 1.5 µm were obtained. Upon thermally treating gallium oxyhydroxide GaO(OH) to 900 °C, β‐Ga₂O₃ was synthesised retaining the initial GaO(OH) morphology. Raman spectroscopy has been used to study the structure of nanorods of GaO(OH) and Ga₂O₃ crystals. Raman spectroscopy shows bands characteristic of GaO(OH) at 950 and ∼1000 cm⁻¹ attributed to Ga OH deformation modes. Bands at 261, 275, 433 and 522 cm⁻¹ are assigned to vibrational modes involving Ga OH units. Bands observed at 320, 346, 418 and 472 cm⁻¹ are assigned to the deformation modes of Ga₂O₆ octahedra. Two sharp infrared bands at 2948 and 2916 cm⁻¹ are attributed to the GaO(OH) symmetric stretching vibrations. Raman spectroscopy of Ga₂O₃ provides bands at 630, 656 and 767 cm⁻¹ which are assigned to the bending and stretching of GaO₄ units. Raman bands at 417 and 475 cm⁻¹ are attributed to the symmetric stretching modes of GaO₂ units. The Raman bands at 319 and 347 cm⁻¹ are assigned to the bending modes of GaO₂ units. Copyright © 2008 John Wiley & Sons, Ltd.     

Molecular mechanism investigation on the interaction of Clothianidin with human serum albumin

Abstract

With the widespread application of neonicotinoid insecticides, Clothianidin has received much attention due to the potential harm to human health and ecological environment. However, the mechanism of Clothianidin's underlying toxicity to organisms remains unclear. In this work, the interaction between Clothianidin and human serum albumin was investigated and the intrinsic fluorescence of human serum albumin got quenched via static mechanisms upon the addition of Clothianidin. The binding constants between Clothianidin and human serum albumin at three different temperature were obtained to be 3.543?×?10⁴, 2.995?×?10⁴, and 2.490?×?10⁴ M^?1, respectively. Based on the van't Hoff equation, the thermodynamic parameters, ΔH⁰ and ΔS⁰ were estimated to be ?53.885?KJ mol^?1 and ?110.535?J mol^?1K^?1, respectively. A single binding site was predicted from the binding constants at different temperatures by multiple spectroscopic techniques and the negative values of ΔH⁰ and ΔS⁰ indicated the binding of human serum albumin with Clothianidin was driven by hydrogen bonds or van der Waals forces. Furthermore, the loose and unfolded secondary structure of human serum albumin along with the addition of clothianidin had been observed through ultraviolet-visible absorption and circular dichroism spectra. In addition, it was also found that Clothianidin had polar effects of structural microenviroment not only on Trp but also Tyr residues from synchronous fluorescence analysis. This study illuminates the molecular mechanism of the interaction between human serum albumin and clothianidin for the first time and helps to construct a specific pesticide biosensor system of human health.     

Prediction of γ‐B28 ELNES with comparison to α‐B12

Using ab initio techniques we have calculated the electron energy loss near edge structure (ELNES) of a new high pressure phase of boron (γ‐B₂₈) and the structurally similar allotrope, α‐B₁₂. The total ELNES spectra are presented as weighted sums of the site specific spectra of the constituent non‐equivalent B atoms. The five different non‐equivalent B sites in γ‐B₂₈ all show rich ELNES spectra and their similarities and differences to the simpler α‐B₁₂ case are detailed. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Electronic transitions in α, θ and γ polymorphs of ultraporous monolithic alumina

Spectroscopy of α, θ, and γ phases of high‐purity ultraporous alumina has been studied at cryogenic temperatures of 7 K in the near‐IR–VUV range of spectra with synchrotron radiation excitation. The UV photoluminescence (PL) spectra are dominated by optical transitions of self‐trapped excitons, while the PL excitation spectra are assigned to free excitons and interband transitions. The analysis of PL excitation spectra indicates a tendency to fundamental bandgap narrowing in order of 9.36 eV (α) to 7.60 eV (θ) and 6.85 eV (γ). Structural defects related to oxygen vacancies are responsible for the visible F⁺/F transitions decrease in order γ > θ > α. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)