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1.
Microsomal prostaglandin E synthase-1 (mPGES-1) is a newly recognized therapeutic target for the treatment of inflammation, pain, cancer, atherosclerosis, and stroke. Many mPGES-1 inhibitors have been discovered. However, as the structure of the binding site is not well-characterized, none of these inhibitors was designed based on the mPGES-1 structure, and their inhibition mechanism remains to be fully disclosed. Recently, we built a new structural model of mPGES-1 which was well supported by experimental data. Based on this model, molecular docking and competition experiments were used to investigate the binding modes of four representive mPGES-1 inhibitors. As the inhibitor binding sites predicted by docking overlapped with both the substrate and the cofactor binding sites, mPGES-1 inhibitors might act as dual-site inhibitors. This inhibitory mechanism was further verified by inhibitor-cofactor and inhibitor-substrate competition experiments. To investigate the potency-binding site relationships of mPGES-1 inhibitors, we also carried out molecular docking studies for another series of compounds. The docking results correlated well with the different inhibitory effects observed experimentally. Our data revealed that mPGES-1 inhibitors could bind to the substrate and the cofactor binding sites simultaneously, and this dual-site binding mode improved their potency. Future rational design and optimization of mPGES-1 inhibitors can be carried out based on this binding mechanism.  相似文献   

2.
Microsomal prostaglandin E synthase-1 (mPGES-1) is a promising target for development of next-generation anti-inflammatory drugs. It is crucial for rational design of the next-generation anti-inflammatory drugs to know the three-dimensional (3D) structure of mPGES-1 trimer and to understand how mPGES-1 binds with substrates and inhibitors. In the current work, a 3D structural model of human mPGES-1 trimer has been developed, for the first time, by performing combined homology modeling, molecular docking, and molecular dynamics simulation. The 3D structural model enables us to understand how mPGES-1 binds with its substrates/inhibitors, and the key amino acid residues for the mPGES-1 binding with ligands have been identified. The detailed 3D structures and calculated binding free energies for mPGES-1's binding with substrates and inhibitors are all consistent with available experimental data, suggesting that the 3D model of the mPGES-1 trimer and the enzyme-ligand binding modes are reasonable. The new structural insights obtained from this study should be valuable for rational design of next-generation anti-inflammatory drugs.  相似文献   

3.
Summary A modelling study has been carried out, investigating the binding of histamine (Hist), 2-methylhistamine (2-MeHist) and 2-phenylhistamine (2-PhHist) at two postulated agonistic binding sites on transmembrane domain 5 (TM5) of the histamine H1-receptor. For this purpose a conformational analysis study was performed on three particular residues of TM5, i.e., Lys200, Thr203 and Asn207, for which a functional role in binding has been proposed. The most favourable results were obtained for the interaction between Hist and the Lys200/Asn207 pair. Therefore, Lys200 was subsequently mutated and converted to an alanine, resulting in a 50-fold decrease of H1-receptor stimulation by histamine. Altogether, the data suggest that the Lys200/Asn207 pair is important for activation of the H1-receptor by histamine. In contrast, analogues of 2-PhHist seem to belong to a distinct subclass of histamine agonists and an alternative mode of binding is proposed in which the 2-phenyl ring binds to the same receptor location as one of the aromatic rings of classical histamine H1-antagonists. Subsequently, the binding modes of the agonists Hist, 2-MeHist and 2-PhHist and the H1-antagonist cyproheptadine were evaluated in three different seven--helical models of the H1-receptor built in homology with bacteriorhodopsin, but using three different alignments. Our findings suggest that the position of the carboxylate group of Asp116 (TM3) within the receptor pocket depends on whether an agonist or an antagonist binds to the protein; a conformational change of this aspartate residue upon agonist binding is expected to play an essential role in receptor stimulation.Abbreviations 2-MeHist 2-methylhistamine - 2-PEA 2-pyridyl-ethylamine - 2-PhHist 2-phenylhistamine - CHO Chinese hamster ovary - Eint interaction energy - Estr strain energy - GES global energy structure - gpH1R guinea pig H1-receptor - GPCR G-protein coupled receptor - Hist histamine - N proximal nitrogen - N tele nitrogen - TM transmembrane domain - WT wild type  相似文献   

4.
Abstract

Shape complementarity, electrostatic and hydrophobic matching, were used to model drugs and receptors. From known experimental data on α1A2A?adrenergic ligands and α1A2A?alrenoceptors, a model for the ligand binding sites, based on the structure of bacteriorhodopsin as a template, was proposed and built. Agonists and antagonists have overlapping but different binding sites. Emphasis was given on the role of the disulphide bridge and on the role of the sodium site. The model was extended to other G-protein coupled receptors.  相似文献   

5.
Mycobacterium tuberculosis 1-deoxy-d-xylulose-5-phosphate reductoisomerase (MtDXR) is a potential target for antitubercular chemotherapy. In the absence of its crystallographic structure, our aim was to develop a structural model of MtDXR. This will allow us to gain early insight into the structure and function of the enzyme and its likely binding to ligands and cofactors and thus, facilitate structure-based inhibitor design. To achieve this goal, initial models of MtDXR were generated using MODELER. The best quality model was refined using a series of minimizations and molecular dynamics simulations. A protein–ligand complex was also developed from the initial homology model of the target protein by including information about the known ligand as spatial restraints and optimizing the mutual interactions between the ligand and the binding site. The final model was evaluated on the basis of its ability to explain several site-directed mutagenesis data. Furthermore, a comparison of the homology model with the X-ray structure published in the final stages of the project shows excellent agreement and validates the approach. The knowledge gained from the current study should prove useful in the design and development of inhibitors as potential novel therapeutic agents against tuberculosis by either de novo drug design or virtual screening of large chemical databases. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.  相似文献   

6.
Within the framework of the density functional theory (DFT), the electronic structure of monooxodioxovanadium functional groups in tetrahedral coordination, which model the active centers (ACs) of fine supported catalysts V2O5/SiO2 and V2O5/TiO2, has been analyzed. The optimal structures of three ACs as possible models of monomeric and polymeric oxovanadium forms on the carriers with low vanadium content were determined. The modified DFT method involving the time dependence of Kohn-Sham equation (TDDFT) was used for the adopted AC models to calculate the energies of the excited states, and optical spectra of the absorption in 25000–60000 cm?1 region were reconstructed on their base. The spectrum in this region is due to O → V charge transfer. The features of electronic spectra with the charge transfer for V2O5/SiO2 and V2O5/TiO2 catalysts and the vibrational spectra of three AC models corresponding to the monomeric and dimeric oxovanadium forms of the supported catalysts V2O5/SiO2 and V2O5/TiO2 were defined. The detailed interpretation of normal vibration frequencies is given. The frequencies typical of the monomeric and dimeric oxovanadium forms on the carrier surface were identified.  相似文献   

7.
The detailed structures of microsomal prostaglandin E synthase-1 (mPGES-1) binding with inhibitors have been studied, for the first time, by using a newly developed computational three-dimensional (3D) structural model of mPGES-1 along with a 3D-quantitative structure--activity relationship (3D-QSAR) analysis. The obtained satisfactory binding structures and 3D-QSAR models strongly suggest that the 3D structural model of mPGES-1 is reasonable for study of mPGES-1 binding with inhibitors and for future design of novel mPGES-1 inhibitors.  相似文献   

8.
Hydroxyl-terminated hyperbranched polyesters (HBPEs) with aromatic/aliphatic structure were synthesized at three different monomer mole ratios (A2/B3=1, 0.9, and 0.6, respectively) by melt polycondensation of isophthalic acid and trimethylolpropane via A2+ B3 approach. Fourier transform infrared (FTIR) spectroscopy indicated that the expected HBPEs, which showed excellent solubility in a variety of polar solvents such as N, N-dimethyl formamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and terahydrofuran (THF), were produced without gelation during the polymerization. The weight-average molecular weight of HBPEs ranged from 7014 to 8306 and their inherent viscosities were varied from 0.17 to 0.34 dL/g. The degree of branching of the HBPEs was estimated to be 0.39–0.49 by1H-NMR and 13C-NMR measurement. Their glass transition temperature measured by differential scanning calorimetry (DSC) was between 64 and 86°C. The thermogravimetric analysis (TGA) measurement revealed that HBPEs had ca 8.5% weight-loss at 300°C in N2.  相似文献   

9.
In this paper, the preparation conditions of antimony-doped SnO2 and PbO2 electrode were optimized for the degradation activity of AO7 dye solution. The results showed that when the doping content of Sb is 8 mol %(SnO2-Sb(0.08)), the SnO2 electrode exhibited best activities for the decolorization and mineralization of AO7. The concentration of NaF in electroplating solution had a noticeable effect on PbO2 electrode for the decolorization of AO7 solution, but little influence on the COD removal rate. The anodic stability tests showed that the electrode prepared in the solution containing 0.10 g l−1 NaF (PbO2-F(0.10)) was best for environmental application. The comparison of SnO2-Sb(0.08), PbO2-F(0.10) and Boron-doped Diamond (BDD) electrodes revealed that a more rapid decolorization rate was obtained on SnO2-Sb(0.08) and PbO2-F(0.10) electrodes in dilute AO7 solutions, while higher COD removal rate of concentrated AO7 solutions was on BDD and SnO2-Sb(0.08) electrodes. The effect of concentration of Na2SO4 on the degradation rate of AO7 was very notable on BDD electrode for its highest overpotential of oxygen evolution reaction. In the chloride-containing medium, the decolorization was accelerated greatly but the completed mineralization of AO7 was inhibited with the increasing of chloride ions concentration when these high-overvoltage anodes were used Published in Russian in Elektrokhimiya, 2008, vol. 44, No. 7, pp. 865–875. The text was submitted by the authors in English.  相似文献   

10.
ABSTRACT

The influence of the presence of an inorganic carrier in the polymerization systems was investigated in this paper. Ten polymerization systems that contained different inorganic carriers such as Al2O3, SiO2 were studied. The ten polymerization systems are dibutyltin Maleate (DBTM) and allyl thiourea (AT), DBTM and stearic acid vinyl ester (SAVE), SAVE and maleic anhydride (MH), SAVE and acrylamide (AM), itaconic acid (IA) and AM, SAVE and IA, AM and MH, IA, sodium acrylate (AANa), AM. It was found that the activity of monomer can be changed in the presence of a carrier and furthermore, the different species of carrier influence the activity of same monomer differently in the polymerization.  相似文献   

11.
Raspberry-like composites were prepared by coating the silver/polypyrrole core/shell composites onto the surface of silica spheres via oxidation polymerization of pyrrole monomer with [Ag(NH3)2]+ ions as oxidants. The whole process allowed the absence of stabilizers, which greatly improved the quality of the conducting polymer composites. The morphology of the resulting composites was investigated, which can be described as raspberry-like; also, the structure and composition of the composites were characterized in detail. A possible formation mechanism was proposed. The present synthetic strategy substantially extended the scope of metal/conducting polymer composite synthesis. The raspberry-like composites exhibited excellent catalytic properties in the reduction of methylene blue dye with the reducing agent of sodium borohydride.  相似文献   

12.
13.
The molecular structure of nickel(II) and copper(II) N,N′-ethylene-bis(acetylacetoneiminates), NiO2N2C12H18 and CuO2N2C12H18, at 442(5) K and 425(5)K, respectively. Both molecules have C 2 symmetry with a nearly planar MN2O2 coordination site and internuclear distances r h1(M-O) = 1.862(10)/1.923(17) Å and r h1(M-N) = 1.879(10)/1.947(18) Å for Ni(acacen) and Cu(acacen), respectively. The structure of free molecules is close to the structure of molecules in crystal. The DFT/3LYP quantum-chemical calculations (CEP-31G and 6-31G* basis sets) gave a molecular structure that agreed satisfactorily with the one found in experiment. The low-spin 1 A and high-spin 3 A states of the Ni(acacen) molecule were considered. It was found that a change in multiplicity caused significant changes in the geometrical and electronic structure of the MN2O2 coordination site. As shown by experiment and calculations for the NiO2N2C12H18 molecule, the low-spin 1 A state is the ground state. The internal rotation of CH3(CN) and CH3(CO) methyl groups was studied by the 3LYP/CEP-31G method. It was shown that steric hindrances led to a high rotation barrier of the CH3(CN) group.  相似文献   

14.
采用分步溶胶-凝胶法制备的三元杂化催化剂TiO2-SiO2-杂多酸(POMs)在可见光降解工业染料罗丹明B中表现出了高效反应活性. 利用时间分辨微波传导(TRMC)和漫反射光谱(DRS)研究了催化剂在可见光区的光催化性能, 实验结果表明: 在三元杂化催化剂内, 二氧化钛和二氧化硅的键合加强了催化剂在可见光区的响应和吸收, 二氧化钛和杂多酸的结合提高了反应活性位(空穴-电子对)的稳定性. 三元杂化催化剂TiO2-SiO2-POMs中组分之间的协同效应促进了可见光光催化性能的提高.  相似文献   

15.
利用同源模建和分子动力学模拟方法构建了人类2-氨基3-羧基粘康酸6-半醛脱羧酶(hACMSD)的三维结构, 并利用Profile-3D和Procheck等方法评估了模型的可靠性. 在此基础上, 用分子对接程序(Affinity), 将其底物2-氨基3-羧基粘康酸6-半醛(ACMS)和抑制剂喹啉酸(QA)分别与hACMSD进行对接, 获得了复合物结构的理论模型. 通过配体与受体之间相互作用能和结构分析给出了底物和抑制剂的具体结合方式, 明确了hACMSD与底物和抑制剂结合时起重要作用的氨基酸残基.  相似文献   

16.
《Analytical letters》2012,45(15):2811-2825
Abstract

Simple and rapid chemiluminescence (CL) assays for H2O2, ?OH, ?O2 ? and 1O2 using 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol) or 2-methyl-6-phenyl-3,7-dihydroimidazo[1,2-α]pyrazin-3-one (CLA) as CL reagents were developed. The means of the intra-assay relative standard deviations of ten replicate measurements of H2O2 (25-120 μM), ?OH generated from Fe(II) ion (2.5-10 μM) in the presence of 980 μM H2O2, ?O2 ? generated from hypoxanthine (HX) (7-50 μM) in the presence of 9 × 10?3 units xanthine oxidase (XO) and 1O2 generated from NaOCl (3-12 mM) in the presence of 97.6 μM H2O2 were found to be 4.0%, 2.8%, 2.4% and 8.7%, respectively. To validate the proposed methods, the scavenging abilities of three standard antioxidative compounds, such as L-ascorbic acid, (±)-α-tocopherol and superoxide dismutase (SOD) were examined for four active oxygen species and compared with those by anelectron spin resonance (ESR) spin-trapping method. In addition, the CL methods were also applied to establish the relationships between the decrease of CL intensity and the structures as well as redox characters of syringic acid, 3-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid. From the obtained results, the scavenging effects to H2O2, ?OH, ?O2 ? and 1O2 of other dihydroxybenzoic acids were also evaluated.  相似文献   

17.
Formation of nano-sized Y2O3-doped CeO2 (YCO) was observed in the chemical reaction between proton conducting Y2O3-doped BaCeO3 (BCY) and CO2 in the temperature range 700-1000 °C, which is generally prepared by wet-chemical methods that include sol-gel, hydrothermal, polymerization, combustion, and precipitation reactions. BCY can capture CO2 of 0.13 g per ceramic gram at 700 °C, which is comparable to that of the well-known Li2ZrO3 (0.15 g per ceramic gram at 600 °C). Powder X-ray diffraction (PXRD), energy dispersive X-ray analysis (EDX), laser particle size analysis (LPSA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and ac impedance spectroscopy were employed to characterize the reaction product obtained from reaction between BCY and CO2 and subsequent acid washing. PXRD study reveals presence of fluorite-like CeO2 (a=5.410 (1) Å) structure and BaCO3 in reaction products. TEM investigation of the acid washed product showed the formation of nano-sized material with particle sizes of about 50 nm. The electrical conductivity of acid washed product (YCO) in air was found to be about an order higher than the undoped CeO2 reported in the literature.  相似文献   

18.
COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors. Fifty-four compounds with tested mPGES-1 inhibitory value were used to develop a model with four pharmacophoric features. 3D-QSAR studies were undertaken to check the robustness of the model. Statistical parameters such as r2 = 0.9924, q2 = 0.5761 and F test = 1139.7 indicated significant predictive ability of the proposed model. Our QSAR model exhibits sites where a hydrogen bond donor, hydrophobic group and the aromatic ring can be substituted so as to enhance the efficacy of the inhibitor. Furthermore, we used our validated pharmacophore model as a three-dimensional query to screen the FDA-approved Lopac database. Finally, five compounds were selected as potent mPGES-1 inhibitors on the basis of their docking energy and pharmacokinetic properties such as ADME and Lipinski rule of five.  相似文献   

19.
Total synthesis of anhydro levuglandin D2 [9-acetyl-8-formyl-5(Z),9(E),11(E)-hepta-decatrienoic acid] confirms the structure assigned to this 9,10-seco prostanoic acid product from solvent induced rearrangement of the prostaglandin endoperoxide PGH2 in aqueous solution.  相似文献   

20.
Ce0.65Zr0.25Y0.1O1.95 oxides were prepared by oxidation-coprecipitation method using ammonia and salvolatile as precipitators. The as-prepared samples were thermally treated at different temperatures and characterized by thermogravimetry-differential scanning calorimetry (TG-DSC), Fourier transform-infrared (FT-IR) spectrometry, X-ray diffraction (XRD), and specific surface area measurements (BET). The results showed that the hydroxyl and carboxyl groups coexisted in the precipitate and a perfect solid solution was gradually formed with an increase in calcination temperature. The physisorbed water was lost from 100 to 170 °C, hydroxyl groups were removed from 250 to 300 °C, and the carboxyl groups were eliminated from 420 to 500 °C. A structure model was further proposed to understand the Ce0.65Zr0.25Y0.1O1.95 structure evolution process in depth.  相似文献   

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