嘧啶衍生物类PI3K/mTOR双重抑制剂的3D-QSAR及分子对接研究

PI3K/Akt/mTOR信号通路在癌细胞的生长和增殖中异常激活,对PI3K和mTOR位点的抑制可有效阻断信号通路的传导,是药物设计的理想靶点.本文选择38个嘧啶类小分子抑制剂进行3D-QSAR和分子对接研究.采用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)方法,建立了三维定量构效关系模型,结果表明,该模型具有良好的稳定性和预测能力,可运用分子对接研究小分子抑制剂与PI3K和mTOR蛋白受体的作用模式.通过对QSAR模型的三维等势图以及受体与配体的相互作用模式分析后,优化出10个小分子化合物并预测其活性,发现一些小分子化合物活性提高,这为PI3K/mTOR双重抑制剂的设计筛选提供了借鉴.     

用分子动力学模拟天然气水合物的抑制效应

用分子动力学模拟方法确定了结构H型(SH)天然气水合物的稳定晶体生长面为(001), 系统研究了277 K时三种动力学抑制剂对此晶面的影响. 模拟显示抑制剂中的氧与表面水分子形成氢键, 从而破坏原有的稳定结构, 造成水合物笼型结构坍塌, 达到抑制水合物形成的效果. 比较三种不同动力学抑制剂对SH的抑制效果得出: PVCap＞PEO＞PVP. 在此基础上研究了PVCap对天然气水合物结构I型(SI), 结构II型(SII)和SH三种不同晶型的抑制效应. 模拟发现抑制效果的次序为: SH＞SI＞SII.     

天然气水合物抑制剂的制备及抑制性能评价

采用溶液聚合法合成了聚乙烯己内酰胺PVCap及共聚物,利用FT-IR和~1H-NMR表征了它们的结构。将动力学抑制剂PVCap、乙烯基己内酰胺-乙二醇共聚物P(VCL-APEG)、乙烯基己内酰胺一含酯单体共聚物P(VCL-A)、聚乙烯吡咯烷酮PVP分别与甲醇进行复配,通过THF方法,研究不同抑制剂对天然气水合物的抑制性能,探讨了动力学抑制剂添加量、复合抑制剂中甲醇添加量等对抑制性能的影响。实验结果表明,甲醇的加入提高了动力学抑制剂的抑制能力,当1%的PVCap、PVP、P(VCL-APEG)、P(VCL-A)分别与5%甲醇复配时,其诱导时间分别可达887min、639min、420min、3300min。     

串联催化体系制备长链支化聚乙烯

利用两种串联催化体系,Cat.I/Cat.II和Cat.I/Cat.III{Cat.I:[ArNCH-C8H3(CH2)2(C6H5)O]2 ZrBn2;Cat.II:(η5-C5Me4)Si(Me)2NtBuTiCl2;Cat.III:tans-Et(Ind)2ZrCl2)},催化了乙烯聚合,一步法制备出了长链支化聚...     

人类胞外信号调节激酶1的同源模建及其抑制剂的对接与结构改造

通过同源模建和分子动力学模拟构建了人类胞外信号调节激酶1(hERK1)的三维结构,并利用profile-3D和procheck方法评估了模型的合理性.对所得的结构使用分子对接程序Affinity和CDOCKER进行了两种抑制剂的对接.结果显示这两种抑制剂与酶的结合方式相似,它们均与残基K36,Q87之间存在氢键作用,二者取代基的不同导致了抑制能力的差别.基于对接结果分析,对已知抑制剂进行结构改造,得到了一个理论上结合能力更强的抑制剂.它在保持与K36和Q87之间氢键的同时,又与残基D93,K96,S135形成了四条氢键,显著提高了与酶的相互作用.对接相互作用能显著下降,MM-PBSA结合自由能降为负值,这些均体现了抑制能力的提高.本工作对于针对该酶的抑制剂设计和相关疾病的新药开发具有理论指导价值.     

分子对接与分子动力学模拟法探究PI3Kδ/度维利塞(Duvelisib)的选择性结合

大量研究表明磷脂酰肌醇3-激酶δ(PI3Kδ)与多种恶性肿瘤及免疫疾病的发生、发展密切相关,因此成为一个备受关注的药物靶点.伊德利塞(Idelalisib),PI3Kδ抑制剂,是首个被FDA批准上市的PI3K抑制剂,以此开启了PI3 Kδ选择性抑制剂开发的热潮,但是严重的毒副作用阻碍了该类化合物的使用.随后,度维利塞(...     

新型吡啶苯磺酰胺联喹啉基异羟肟酸类PI3K/HDAC双靶点抑制剂的设计、合成和生物活性研究

多靶点药物已成为一种有广阔前景的药物,特别是对抗肿瘤药物的研发.基于候选药物GSK2126458和上市药物Vorinostat的结构特点,设计并合成了一系列新型的磷脂酰肌醇3-激酶(PI3Ks)和组蛋白脱乙酰酶(HDACs)双重抑制剂.生物活性研究发现,化合物GYB-4对PI3Kα和HDAC1的IC50分别为1.0和4.2nmol/L;化合物GYB-5对PI3Kα和HDAC1的IC50分别为1.3和4.8nmol/L.对所有化合物在HCT116,PC3和A2780细胞株上进行了增殖抑制活性研究,相关的构效关系研究将为PI3K和HDAC双靶点抑制剂的进一步优化提供思路.     

新型吡啶苯磺酰胺联喹啉基异羟肟酸类PI3K/HDAC双靶点抑制剂的设计、合成和生物活性研究（英文）

多靶点药物已成为一种有广阔前景的药物,特别是对抗肿瘤药物的研发.基于候选药物GSK2126458和上市药物Vorinostat的结构特点,设计并合成了一系列新型的磷脂酰肌醇3-激酶(PI3Ks)和组蛋白脱乙酰酶(HDACs)双重抑制剂.生物活性研究发现,化合物GYB-4对PI3Kα和HDAC1的IC50分别为1.0和4.2nmol/L;化合物GYB-5对PI3Kα和HDAC1的IC50分别为1.3和4.8nmol/L.对所有化合物在HCT116,PC3和A2780细胞株上进行了增殖抑制活性研究,相关的构效关系研究将为PI3K和HDAC双靶点抑制剂的进一步优化提供思路.     

催化剂Ce-SO2-4/SBA-15的固相合成及其催化性能

以介孔分子筛SBA-15为载体,采用固相研磨法将Ce和SO2-4 同时掺杂在SBA-15中,合成了Ce-SO2-4/SBA-15负载型催化剂(Cat).用IR, XRD, TEM,低温N2吸附-脱附,TG和NH3-TPD等方法对Cat的结构性质及其表面酸性进行了研究.结果表明,Cat保持高度有序的一维六方介孔结构,且具有弱酸中心和中强酸中心.用Hammett指示剂法测得其表面酸强度为0.99～1.80,表明Cat为固体酸.将Cat用于催化合成乙酸正丁酯,正交实验结果表明:在冰乙酸0.126 mol, n(冰乙酸): n(正丁醇)=1.0 : 1.2, Cat 375 mg,回流反应140 min的较佳反应条件下,酯化率达97.45%.     

Pt-Rh/CeZrYLa+LaAl催化剂用于理论空燃比天然气汽车尾气净化

采用共沉淀法制备了CeZrYLa+LaAl纳米复合载体,以三种方法制备了一系列Pt-Rh/CeZrYLa+LaAl催化剂.对所制样品进行了N2吸附-脱附、粉末X射线衍射、X射线光电子能谱和H2程序升温还原的表征.并考察了三种方法所制得催化剂的理论空燃比天然气汽车尾气净化性能.结果表明,三个催化剂的活性顺序为Cat3≈ Cat2> Cat1,其中Cat3具有最低的CO和NO起燃温度(T50),分别为114oC和149 oC,最低的CH4和CO完全转化温度(T90),分别为398 oC和179 oC,以及最佳的CH4和CO温度特性,ΔT (T90–T50)值分别为34 oC和65 oC. Cat2具有最低的CH4起燃温度(342°C)和最低的NO完全转化温度(174°C). Cat1具有最差的转化活性,说明物理混合法制备的催化剂(Cat3和Cat2)性能优于共浸渍法制备的催化剂(Cat1).这是由于物理混合法制备的催化剂, Pt和Rh均匀分散在载体表面,两者物理接触共同参与CH4/CO/NO三种污染物的转化.相反,共浸渍法制备的催化剂, Pt和Rh之间存在较强的相互作用,改变了Pt的电子状态,而且形成了表面Pt富集的Pt-Rh双金属颗粒覆盖了Rh活性位,从而降低催化活性;同时,对于通过物理混合法并进一步添加助剂所制备的Cat3, XRD结果显示助剂Zr4+进入了铈锆固溶体晶格,产生晶格缺陷; XPS结果显示Cat3具有最高的Ce3+/Ce比例.这些都有利于提高催化剂的氧流动性,从而提高催化剂活性并拓宽空燃比窗口.     

Fluoresence quenching of riboflavin in aqueous solution by methionin and cystein

The fluorescence quantum distributions, fluorescence quantum yields, and fluorescence lifetimes of riboflavin in methanol, DMSO, water, and aqueous solutions of the sulphur atom containing amino acids methionin and cystein have been determined. In methanol, DMSO, and water (pH=4–8) only dynamic fluorescence reduction due to intersystem crossing and internal conversion is observed. In aqueous methionin solutions of pH=5.25–9 a pH independent static and dynamic fluorescence quenching occurs probably due to riboflavin anion–methionin cation pair formation. In aqueous cystein solutions (pH range from 4.15 to 9) the fluorescence quenching increases with rising pH due to cystein thiolate formation. The cystein thiol form present at low pH does not react with neutral riboflavin. Cystein thiolate present at high pH seems to react with neutral riboflavin causing riboflavin deprotonation (anion formation) by cystein thiolate reduction to the cystein thiol form.     

Enzymes of Opuntia ficus-indica (L.) Miller with potential industrial applications-I

We report on the screening of different enzymes such as arylamidases, lipases, proteinases, and glucosidases in plant extracts of the Cactaceae family, genus Opuntia, as well as on a newly purified plant proteases from O. ficus-indica fruit extracts. These proteinases showed the maximum activity at pH 5.2 and 55°C and FTC-casein was the best of the escreened substrates. Proteolytic activities were activated by anti-oxidant compounds and by some divalent cations. These proteinases were efficiently inhibited by cystein proteinase inhibitors and by 1,10-phenanth roline. The estimated M _t for the main proteolytic activity was about 23.2 kDa. The results on milk clotting characteristics suggest a potential use of the fruit cystein enzymes of this plant in dairy industries.     

Palladium catalyzed thiol cross-coupling of cystein derivatives with aryl and alkenyl halides

Palladium catalyzed cystein thiol cross-coupling reactions with aryl and vinyl halides have been investigated: Pd₂dba₃-CHCl₃ and dppf are the key choice in these reactions. The role of the base in these reactions was also questioned: it has been shown that base can be replaced by an HX-scavenger such as propylene oxide.     

猴金属硫蛋白MT1 α-结构域中Cys33和Cys34的突变对蛋白质稳定性的影响

重组猴金属硫蛋白MT1及其C33M,C34S和C33M/C34S突变体蛋白的蛋白质快速液相色谱(FPLC)分析表明,突变体蛋白C34S和C33M/C34S存在着两个稳定的流分f1和f2.CD光谱和重金属离子分析表明,突变体蛋白多流分不仅与半胱氨酸和Cd2+离子结合方式和构型有关,还与金属结合量有关.突变体蛋白多流分的结果表明,在把猴金属硫蛋白α-结构域中的Cys33和Cys34突变为非半胱氨酸残基以建立β-β结构域的金属硫蛋白时,可导致蛋白形成多种结构形式.这表明α-结构域在稳定金属硫蛋白的结构中起着重要的作用,半胱氨酸残基在肽链上的分布对金属硫蛋白的三级结构和金属硫簇的形成有重大的影响.     

Enzymatic determination of some pharmaceuticals in direct and reversed sodium dodecyl sulfate micelles

The properties of horseradish peroxidase in sodium dodecyl sulfate (DDS) reversed micelles in benzene-pentanol-water solutions are studied. The potential of the analytical application of direct and reversed DDS micelles is demonstrated using newly developed methods for the determination of peroxidase substrates (hydrogen peroxide and cystein), inhibitor (sulfanylamide), and activator (imidazole) via the oxidation of o-dianisidine (o-D) with hydrogen peroxide.     

Gold nanoparticles as a colorimetric sensor for protein conformational changes

Spherical gold nanoparticles and flat gold films are prepared in which yeast iso-1-cytochrome c (Cyt c) is covalently bound to the gold surface by a thiol group in the cystein 102 residue. Upon exposure to solutions of different pH, bound Cyt c unfolds at low pH and refolds at high pH. This conformational change causes measurable shifts in the color of the coated nanoparticle solutions detected by UV-VIS absorption spectroscopy and in the refractive index (RI) of the flat gold films detected by surface plasmon resonance (SPR) spectroscopy. Both experiments demonstrate the same trend with pH, suggesting the use of protein-covered gold nanoparticles as a simple colorimetric sensor for conformational change.     

Electrical and magnetic properties of some organic charge transfer complexes

Two 7,7,8,8-tetracyanoquinodimethane (TCNQ) complexes with cystein and guanine have been investigated. EPR spin signals of these charge transfer complexes were recorded and the electron spin lattice relaxation time (T₁) temperature dependence was investigated. The electron scattering time, calculated from T₁, agreed reasonably well with that from the current carrier effective mass (as determined through the Hall mobility measurements).     

The Use of the O-Nitrocinnamoyl Group as an Amine Blocking Function

The thiomethylene oxazolone I is, in principle, a useful synthon for the preparation of 2-substituted cystein derivatives II. However, the benzamide group cannot be removed easily in the presence of other sensitive functionalities. Since compounds of type I have only been described when the substituent at C-2 is phenyl,¹ and since there is no reason to believe that compounds of type I with an aliphatic substituent at C-2 are very stable, we thought that the o-nitrocinnamoyl group might be a suitable substituent because of its aromatic character and its similarity to the o-nitrophenoxyacetic group, which has been successfully used as an easily removable amine blocking function.² We therefore prepared o-nitrocinnamoyl glycine III and converted it via the ethoxymethylene derivative IVa to the sodium salt of the 4-thiomethylene derivative IVb, which is a stable compound.     

Exciting flavins: Absorption spectra and spin–orbit coupling in light–oxygen–voltage (LOV) domains

Flavins are central molecular chromophores for many photobiological processes. In this paper, several aspects of the photophysics and photochemistry of lumiflavin in a (protein) environment will be studied with the help of quantum chemical methods. In a first part of the paper, we present vertical singlet excitation energies for lumiflavin (a molecule of the isoalloxazin type), using time-dependent density functional theory (TD-DFT) in conjunction with the B3LYP hybrid functional. When calculated for isolated species, TD-DFT excitation energies are generally blue-shifted relative to the experimental absorption spectra of isoalloxazines in solution, or in a protein environment. We develop four different models to account for environmental effects, with special emphasis on the LOV1 domain of Chlamydomonas reinhardtii. It is found that the two lowest, allowed singlet excitations are sensitive to the polarizability of an environment, to hydrogen bonds, and to geometrical constraints imposed by the surrounding protein. All of this brings theory and experiment in better agreement.

In the second part of the paper the light-induced adduct formation in LOV domains, between the chromophore and a neighbouring cystein unit is investigated. Energies along a model “reaction path” are calculated on the DFT/B3LYP and MCQDPT2 level of theories. A transition state for a H-transfer between the mercapto (SH–) group of cystein, and the N(5) position of flavin is found. The reaction requires spin–orbit coupling between the S₀ and the T₁ states of the system. Spin–orbit coupling constants between S₀ and T₁ are calculated, and found to be in the range of several tens of cm⁻¹ after the transition state was passed. A biradical intermediate was observed along the reaction path.     

Interactions of glutathione tripeptide with gold cluster: influence of intramolecular hydrogen bond on complexation behavior

Understanding the nature of the interaction between metal nanoparticles and biomolecules has been important in the development and design of sensors. In this paper, structural, electronic, and bonding properties of the neutral and anionic forms of glutathione tripeptide (GSH) complexes with a Au(3) cluster were studied using the DFT-B3LYP with 6-31+G**-LANL2DZ mixed basis set. Binding of glutathione with the gold cluster is governed by two different kinds of interactions: Au-X (X = N, O, and S) anchoring bond and Au···H-X nonconventional hydrogen bonding. The influence of the intramolecular hydrogen bonding of glutathione on the interaction of this peptide with the gold cluster has been investigated. To gain insight on the role of intramolecular hydrogen bonding on Au-GSH interaction, we compared interaction energies of Au-GSH complexes with those of cystein and glycine components. Our results demonstrated that, in spite of the ability of cystein to form highly stable metal-sulfide interaction, complexation behavior of glutathione is governed by its intramolecular backbone hydrogen bonding. The quantum theory of atom in molecule (QTAIM) and natural bond orbital analysis (NBO) have also been applied to interpret the nature of interactions in Au-GSH complexes. Finally, conformational flexibility of glutathione during complexation with the Au(3) cluster was investigated by means of monitoring Ramachandran angles.