分子对接研究β-受体阻滞剂及其类似物毛细管电泳手性识别机理

利用分子对接软件AutoDock程序计算了羟丙基-β-环糊精与β-受体阻滞剂心得安及5种类似物相互作用的结合自由能.结果表明:结合自由能的大小与迁移时间长短的顺序一致;结合自由能差异值的绝对值的大小与手性选择性因子、分离度大小顺序一致,正确反映了羟丙基-β-环糊精对β-受体阻滞剂心得安及5种类似物对映体的R/S识别顺序...     

多溴代二苯胺热力学性质的密度泛函理论研究

在B3LYP/6-31G*水平上对209个多溴代二苯胺(PBDPA)系列化合物进行了全优化和振动分析计算, 得到各分子在298.15 K, 101.3 kPa标准状态下的热力学参数. 设计等键反应, 计算了PBDPA系列化合物的标准生成热(ΔfHÖ)和标准生成自由能(ΔfGÖ). 研究了热力学参数SÖ与溴原子的取代位置及取代数目(NPBS)之间的关系, 结果表明: PBDPA系列化合物的SÖ, ΔfHÖ和ΔfGÖ与NPBS之间有很强的相关性(R2≥0.984). 根据异构体标准生成自由能的相对大小, 从理论上求得异构体的相对稳定性. 以Gaussian 03程序的输出文件为基础, 采用统计热力学程序计算了PBDPA化合物在200 K至1000 K的摩尔恒压热容(Cp,m), 并用最小二乘法求得Cp,m与温度之间的相关方程, 发现Cp,m与T, T－1和T－2之间有着很好的相关性(R2＝1.000).     

多氟代、多氯代和多溴代二苯并对二噁英化合物的一些性质的比较研究

采用密度泛函理论(DFT)方法, 在B3LYP/6-311G**和B3LYP/6-31G*两种水平上, 对76种多氟代二苯并对二噁英系列化合物(PFDDs)进行了几何构型的全优化, 并计算了各分子在298.15 K, 1.013×10⁵ Pa的标准状态下的热力学参数. 基组从6-31G*增大到6-311G**没有显著改变标准生成热(Δ_fH^?)、标准生成自由能(Δ_fG^?)和标准熵(S^?)数值. 根据B3LYP/6-311G**水平计算得到的Δ_fG^?的相对大小, 求得PFDDs同数目取代氟原子的各异构体的相对稳定性的顺序. 采用基团贡献法计算了多溴代二苯并对二噁英(PBDDs)、多氯代二苯并对二噁英(PCDDs)和PFDDs的辛醇-水分配系数(lg K_ow). 并将PFDDs的Δ_fH^?, Δ_fG^?, S^?和lg K_ow的计算结果与PBDDs和PCDDs的相关数值进行了比较. 同时, 计算了PFDDs各组异构体化合物的生成反应相对速率常数, 采用统计热力学程序计算了这些化合物在200至1800 K的恒压摩尔热容(C_p,m), 并用最小二乘法求得C_p,m与温度之间的相关方程, 发现C_p,m与T, T^－1和T^－2之间有着很好的相关性.     

乙酰胆碱酯酶与抑制剂分子对接的ABEEMσπ/MM研究

应用ABEEMσπ/MM方法,对乙酰胆碱酯酶抑制剂Tacrine(塔克宁)与组胺转甲基酶进行了分子对接.然后对乙酰胆碱酯酶与4种乙酰胆碱酯酶抑制剂的分子对接进行了研究.在研究中将受体分子固定,配体分子可自由移动,采用半柔性对接方式.通过对4种乙酰胆碱酯酶抑制剂与乙酰胆碱酯酶结合能大小的计算,得到结合能力大小顺序依次为:Donpezil(多奈哌齐)＞Huperzine(石杉碱甲)＞Rivastigmine(利发斯的明)＞Tacrine(塔克宁).这个顺序与实验中得到的乙酰胆碱酯酶(AChE)抑制活性IC50值大小顺序相一致.为使用该方法进行抑制剂设计提供参考.     

萘酰亚胺类电荷转移化合物能隙的理论研究

采用TD-DFT的最优Hartree-Fock(HF)交换方法, 计算以1,8-萘酰亚胺为受体(A), 9,9-二甲基-9,10-二氢吖啶、吩噁嗪等为给体(D)构建的12种分子内电荷转移化合物的最低激发单重态和最低激发三重态的能级差(ΔE_ST), 并探寻降低ΔE_ST的方法. 结果表明: D-A型分子比相应的D-苯桥-A型分子具有更低的ΔE_ST. 增加D与A间的扭曲二面角(空间位阻)和提高D的给电子能力能够有效地降低D-A型分子的ΔE_ST. 计算发现4-(9,9-二甲基-9,10-二氢吖啶)-N-苯基-1,8-萘酰亚胺(4b)和4-(吩噁嗪)-N-苯基-1,8-萘酰亚胺(5b)的ΔE_ST分别为0.01和0.02 eV, 它们的起始荧光波长分别为575 nm和621 nm, 垂直激发的振子强度分别是0.0002和0.0025. 这两种化合物有望成为发橙红光和红光的热激活延迟荧光材料.     

烷基芳基磺酸盐结构对微乳液热力学性质的影响

用稀释法研究了自制的6种不同结构的烷基芳基磺酸盐(AAS)在多组分体系中形成微乳液的标准热力学函数,并考察了分子结构、温度、短链醇、含水量和无机盐含量对其的影响。 结果表明,随着烷基芳基磺酸盐分子长烷基链碳原子数的增加,导致表面活性剂/正丁醇/正癸烷/水形成的微乳液体系中醇由油相转移到界面相的标准自由能ΔG0o→i减小,有利于微乳液的形成;ΔH0o→i无明显变化,ΔS0o→i增大,且与烷基链碳原子数呈线性关系。 ΔS0o→i=1.7975n+71.538。 随着表面活性剂分子芳环向烷基链中间位置移动,导致表面活性剂/正丁醇/正癸烷/水形成的微乳液体系中醇由油相转移到界面相的标准自由能ΔG0o→i减小,有利于微乳液的形成;ΔS0o→i增大,ΔH0o→i减小;温度的升高导致微乳液体系的ΔG0o→i减小,微乳液的形成更容易。随醇碳链上碳原子数增加,ΔG0o→i减小,有利于微乳液的形成,且ΔG0o→i与碳原子数n呈线性关系,ΔG0o→i=-2790.8n+7286.4(328 K);含水量的增加导致ΔG0o→i增大,不利于微乳液的形成,且ΔG0o→i与含水量V也呈线性关系。 ΔG0o→i=6697.8V-7170.4(318 K);无机盐浓度的增加导致ΔG0o→i减小,有利于微乳液的形成。     

量子化学计算解析手性共价有机框架材料6色谱固定相的手性拆分机理

为探究手性共价有机框架材料6(Chiral Covalent Organic Frameworks 6, CCOF6)色谱固定相的手性拆分机理,首先运用ORCA程序对CCOF6及4对手性对映体进行结构优化,然后使用AutoDock程序对CCOF6及各对映体分子进行分子对接,获得CCOF6与对映体相互作用的初始构型;采用ORCA程序(B3LYP泛函,带DFT-D3校正,轨道基组为def2-TZVP, def2/J作为RI-J的辅助基组,RIJCOSX用来加速计算)对初始构型进行能量计算,以最终确定CCOF6与对映体的相互作用构型,并获得相应的结合自由能和结合自由能差;使用Multiwfn程序对ORCA结果进行独立梯度模型分析,并应用视觉分子动力学程序可视化展示CCOF6与对映体的弱相互作用。结果表明:①在计算结合自由能方面,考虑了溶剂效应的ORCA计算方法比不考虑溶剂效应的ORCA以及AutoDock计算方法更为精确;②CCOF6色谱固定相与对映体之间的结合自由能差绝对值越大,对映体的选择性因子也越大,然而对映体的分离度不一定会越大;③除S-1-苯基-1-丙醇是以羟基和CCOF6的醚键发生相互作用外,其他对映体皆为羟基与CCOF6的羰基发生相互作用,且S-1-苯基-1-丙醇与CCOF6的结合力最弱;④结合对映体的出峰时间和其与CCOF6的结合自由能大小可以推断,正己烷/异丙醇流动相对1-苯基-1-丙醇的洗脱能力最弱,正己烷/异丙醇流动相对1-苯基-2-丙醇的洗脱能力次弱;⑤除了S-1-苯基-1-丙醇出峰时间迟于R-1-苯基-1-丙醇,其余对映体均为R型出峰时间迟于S型。     

氟代索拉非尼的合成及其抗肿瘤活性研究

以N-甲基-4-氯-2-吡啶甲酰胺为原料,经过4步共合成4个化合物(S-1,S-2,R-1和R-2),其中2个为新的化合物(S-1和R-2)。经过1H NMR,13C NMR,HR-MS等方法对其结构表征。最后通过CTG法,测试4种化合物对四种人肝癌细胞(PLC/PRF/5,Hep3B,HepG2,BEL-7402)的抑制活性。结果表明:S-1,S-2,R-1和R-2均表现较明显的对4种细胞的抑制活性,且呈现出浓度依赖关系。IC50值从1304nM到11228nM。其中化合物R-1(瑞格非尼)对PLC/PRF/5和HepG2细胞,S-1对Hep3B细胞的抑制活性,R-2对HepG2的细胞活性均较高于原药索拉非尼。     

基于计算机模拟技术对JAK2抑制剂的定量构效关系、分子设计和分子动力学研究

本文选取了52个对Janus激酶2(JAK2)有抑制作用的小分子化合物,分别使用3D-QSAR中的CoMFA和CoMSIA方法构建了两个可靠的、具有预测能力的模型,并利用分子对接分析数据集化合物与JAK2蛋白的相互作用,表明化合物主要通过氢键和范德华作用与JAK2靶蛋白结合。根据3D-QSAR模型的分析结果,设计了40个化合物,利用构建的模型预测其抑制活性;使用软件预测了化合物的药代动力学(ADME)参数,开展分子对接模拟,最终选择化合物D01和D22与JAK2靶蛋白进行了分子动力学模拟研究,结果显示两个复合物结合构象稳定,与分子对接结果趋势一致。本研究的结果可以为JAK2抑制剂的研发提供一些新的思路,为临床开发此类药物提供理论支撑。     

酪氨酸蛋白磷酸酯酶1B抑制剂的分子对接和三维定量构效关系研究

用一种柔性分子对接方法(FlexX)将12个2-草酰胺苯甲酸类抑制剂和酪氨酸蛋白磷酸酯酶(PTP1B)活性口袋进行分子对接,对接程序预测的抑制剂和酶之间的相互作用能与抑制活性之间有很好的相关性(非线性相关系数R²达0.859),这说明对接结果可以比较准确地预测抑制剂和PTP1B之间的结合模式.然后,将33个同类抑制剂的骨架叠合在分子对接预测的结合构象上,用比较分子力场分析方法(CoMFA)对其进行三维定量活性构效关系研究,得到的CoMFA模型具有很好的统计相关性(交互验证回归系数q²为0.650),并可以准确地预测测试集6个化合物的活性(平均标准偏差为0.177).同时,由CoMFA模型得出的抑制剂改造信息与用FlexX预测的结合模式是一致的,进一步证明我们预测的结合模式是正确的.为研究这类抑制剂和PTP1B的结合模式及对抑制剂进行结构改造提供了信息.     

Short-range interactions within molecular complexes formed in supersonic beams: structural effects and chiral discrimination

One- and two-color, mass-selected R2PI spectra of the S1<--S0 transitions in the bare chiral chromophore R-(+)-1-phenyl-1-propanol (R) and its complexes with a variety of alcoholic solvent molecules (solv), namely methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, S-(+)-2-butanol, R-(-)-2-butanol, 1-pentanol, S-(+)-2-pentanol, R-(-)-2-pentanol, and 3-pentanol, were recorded after a supersonic molecular beam expansion. Spectral analysis, coupled with theoretical calculations, indicate that several hydrogen-bonded [R.solv] conformers are present in the beam. The R2PI excitation spectra of [R.solv] are characterized by significant shifts of their band origin relative to that of bare R. The extent and direction of these spectral shifts depend on the structure and configuration of solv and are attributed to different short-range interactions in the ground and excited [R.solv] complexes. Measurement of the binding energies of [R.solv] in their neutral and ionic states points to a subtle balance between attractive (electrostatic and dispersive) and repulsive (steric) forces, which control the spectral features of the complexes and allow enantiomeric discrimination of chiral solv molecules.     

Theoretical study of β and γ-cyclodextrins inclusion complexes with nineteen atropisomeric polychlorobiphenyls

Inclusion complexes of β and γ-cyclodextrins (CDs), chirally selective macrocycles, with 19 atropisomeric polychlorinated biphenyls (PCBs), stable at physiological temperatures, were studied by molecular mechanics optimized potential for liquid simulations and semi-empirical quantum AM1 methods. Bimodal manual docking, geometry optimization and single point calculations were done. PCB:CD complex formation was studied considering two ways of entry in the large base of CD cavity: with biphenyl C1–C1′ bond axis of PCBs oriented parallel and anti-parallel with the CD trunk height axis. A distance dependent dielectric constant was used to account for the solvent effect. The values of complexation and binding energies were calculated, confirming the existence of a specific van der Waals (vdW) type interaction. β and/or γ-CD chiral recognition of the 19 atropisomeric PCBs, is described by means of the complexation and binding energy values. The binding energy is a better discriminator of PCBs enantiomers than complexation energy considering the average energy differences between (+) and (?) PCB:β/γ-CD complexes. The chromatographic elution order of several PCB enantiomers from literature was correlated with the complexation and binding energies. The molecular modeling of inclusion complexes is recommended to be used as enantiomer identification tool in correlation with chromatographic data.     

Direct high-performance liquid chromatographic enantioseparation of free α-, β- and γ-aminophosphonic acids employing cinchona-based chiral zwitterionic ion exchangers

We report a chiral high-performance liquid chromatographic enantioseparation method for free α-aminophosphonic, β-aminophosphonic, and γ-aminophosphonic acids, aminohydroxyphosphonic acids, and aromatic aminophosphinic acids with different substitution patterns. Enantioseparation of these synthons was achieved by means of high-performance liquid chromatography on CHIRALPAK ZWIX(+) and ZWIX(-) (cinchona-based chiral zwitterionic ion exchangers) under polar organic chromatographic elution conditions. Mobile phase characteristics such as acid-to-base ratio, type of counterion, and solvent composition were systematically varied in order to investigate their effect on the separation performance and to achieve optimal separation conditions for the set of analytes. Under the optimized conditions, 32 of 37 racemic aminophosphonic acids studied reached baseline separation when we employed a single generic mass-spectrometry-compatible mobile phase, with reversal of the elution order when we used (+) and (-) versions of the chiral stationary phase.

Use of NMR binding interaction mapping techniques to examine interactions of chiral molecules with molecular micelles

NMR spectroscopy was used to investigate the association of four chiral molecules with the molecular micelle poly(sodium N-undecanoyl-l-leucylvalinate) (poly(SULV)). Adding poly(SULV) to the background electrolyte in electrokinetic chromatography (EKC) allows enantiomeric resolution to be achieved because enantiomers interact differentially with the chiral centers on the micelle headgroups as they both move in the electric field. Pulsed field gradient diffusion experiments were used to measure molecular micelle association constants for enantiomers of each analyte. These association constants were consistent with EKC elution order for the compounds 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BNP), 1,1'-bi-2-naphthol (BOH), and Troger's base. In addition, nuclear Overhauser enhancement spectroscopy, nuclear Overhauser effect difference, and intermolecular cross relaxation diffusion experiments were used to generate binding interaction maps for each chiral analyte. These maps showed that BNP and BOH inserted into the surfactant headgroup's major chiral groove and interacted predominately with the leucine chiral center. (+)-Troger's base was also found to insert into the major chiral groove. However, this compound instead interacted with the valine chiral atom. In diffusion experiments with long diffusion times, the linearized diffusion plots for each analyte-molecular micelle mixture showed curvature characteristic of intermolecular cross relaxation. The magnitude of this effect scaled linearly with the analytes' free energies of binding.     

高效液相色谱-串联质谱法分析毛发中甲基苯丙胺和苯丙胺手性对映异构体

建立了高效液相色谱-串联质谱（HPLC-MS/MS）分析毛发中甲基苯丙胺与苯丙胺对映异构体的手性分离方法。采用SUPELCO Astec CHIROBIOTIC^® V2手性液相色谱柱,以甲醇-含0.1%（v/v）甲酸的20 mmol/L乙酸铵水溶液（99：1,v/v）为流动相进行手性分离。结果表明,甲醇高温水浴超声法能较好地提取苯丙胺类化合物,且峰形较好（拖尾因子>0.95）。S-（+）-甲基苯丙胺、R-（-）-甲基苯丙胺、S-（+）-苯丙胺和R-（-）-苯丙胺在15~300 ng/mg范围内线性关系良好,相关系数均大于0.99;甲基苯丙胺和苯丙胺的检出限分别为0.1 ng/mg和0.15 ng/mg,定量限分别为0.4 ng/mg和0.5 ng/mg;日内精密度均≤6.8%,日间精密度均≤11.4%。采用所建方法对50余嫌疑人毛发进行手性分析,检出单一S-（+）-甲基苯丙胺和S-（+）-苯丙胺的占70%,同时检出S-（+）-甲基苯丙胺、R-（-）-甲基苯丙胺、S-（+）-苯丙胺和R-（-）-苯丙胺的占18%。该法简单快速,精密度好,可为实际法医毒物鉴定案例中的毛发手性分析提供技术支持与科学依据。     

Enantioselective binding of α-pinene and of some cyclohexanetriol derivatives by cyclodextrin hosts: A molecular modeling study

We have used molecular modeling to investigate the enantioselective separation of the monoterpene α-pinene on permethylated β-cyclodextrin and on α-cyclodextrin and the enantioselective separation of three cyclohexanetriol derivatives on permethylated β-cyclodextrin. Using the Consistent Valence Force Field (CVFF) from Insight/Discover, we have carried out systematic rigid-body docking grid searches on each of the optical antipodes of the organic guest molecules interacting with the cyclodextrins, followed by minimizations of the low-energy docked structures. A statistical mechanical analysis of the minimized energies yields data that agree in four out of five cases with the experimental elution order of enantiomers. The computed energies of the rigid-body docking before minimizations do not agree with the experimental results, suggesting that a conformational induced fit of the cyclodextrins upon binding of the organic guests may be involved in the mechanism of the chiral recognition. © 1996 by John Wiley & Sons, Inc.     

Characterization of the stereoselective metabolism of thiopental and its metabolite pentobarbital via analysis of their enantiomers in human plasma by capillary electrophoresis.

Using capillary zone electrophoresis (CZE) with a 75 mM phosphate buffer at pH 8.5 containing 5 mM hydroxypropyl-gamma-cyclodextrin (OHP-gamma-CD) as chiral selector, the separation of the enantiomers of thiopental and its oxybarbiturate metabolite, pentobarbital, is reported. Enantiomer assignment was performed via preparation of enantiomerically enriched fractions using chiral recycling isotachophoresis (rITP) processing of racemic barbiturates and analysis of rITP fractions by chiral CZE and circular dichroism spectroscopy. Thiopental and pentobarbital enantiomers in plasma were extracted at low pH using dichloromethane and extracts were reconstituted in acetonitrile or 10-fold diluted, achiral running buffer. The stereoselectivity of the thiopental and pentobarbital metabolism was assessed via analysis of 12 plasma samples that stemmed from patients undergoing prolonged or having completed long-term racemic thiopental infusion. The data obtained revealed a modest stereoselectivity with R-(+)-thiopental/S-(-)-thiopental and R-(+)-pentobarbital/S-(-)-pentobarbital plasma ratios being < 1 (P < 0.05 compared to data obtained with racemic controls) and > 1 (P < 0.001), respectively. The total S-(-)-thiopental plasma concentration was found to be on average about 24% higher compared to the concentration of R-(+)-thiopental, whereas the total R-(+)-pentobarbital plasma level was observed to be on average 29% higher compared to the S-(-)-pentobarbital concentration.     

Inclusion of Enantiomeric Carvones in β-Cyclodextrin: a Variable Temperature 1H NMR Study in Aqueous Solution

In aqueous solution, the apparent association constant at room temperature for the 1 : 1 inclusion of S-(+)-carvone in - cyclodextrin is double of that for R-(-)-carvone, whereas, at 45 °C, both enantiomers have association constants two orders of magnitude smaller, with the S-(+) inclusion being then slightly weaker than the R-(-) encapsulation. Calculations carried out at the molecular mechanics, AM1 and STO-3G levels confirm the preferential inclusion of the S-enantiomer and provide important clues for understanding chiral discrimination by -cyclodextrin.     

Chiral characterization of deprenyl-N-oxide and other deprenyl metabolites by capillary electrophoresis using a dual cyclodextrin system in rat urine

A chiral capillary electrophoresis method has been developed for the simultaneous separation of the enantiomers of deprenyl and eight of its metabolites, among them the recently described metabolite deprenyl-N-oxide. Although heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) was suitable for the enantioresolution of deprenyl and its dealkylated derivatives, the enantiomers of deprenyl-N-oxide were just partly resolved. Carboxymethyl-beta-cyclodextrin (CMBCD) in as low as 2 mM concentration was capable of the enantiomer separation of all the nine examined compounds, however co-migration of 1R,2S-(-)-norephedrine and 1R,2R-(-)-pseudoephedrine, as well as 1S,2R-(+)-ephedrine and R-(-)-amphetamine was observed. This problem could be overcome by the use of a dual cyclodextrin system containing 4 mM DIMEB in addition to 2 mM CMBCD; simultaneous separation of all the compounds could be achieved. The optimized method was used for the analysis of rat urine samples after 10 days of treatment of animals with either R-(-)- or S-(+)-deprenyl. The stereospecific biotransformation of both deprenyl enantiomers was confirmed, and the stereoselectivity of N-oxide formation was demonstrated.     

Determination of saterinone enantiomers in plasma samples with an internal standard using a Chiralcel OD column, fractionation and reversed-phase chromatography

A specific and validated high-performance liquid chromatographic method was developed for the determination of the S-(-) and R-(+) enantiomers of saterinone. 1-[(4-cyano-1,2-dihydro-6-methyl-2-oxopyridin-5-yl)phenoxyl] -3-[4-(2- methoxyphenyl)piperazin-1-yl]propan-2-ol, in plasma at the low ng/ml level. The enantiomers of saterinone and an internal standard, 1-[(4-cyano-1,2-dihydro-6-methyl-2-oxo-pyridin-5-yl)phenoxy]-3-[4-(2- ethoxyphenyl)piperazin-1-yl]propan-2-ol, were chromatographed on a chiral Chiralcel OD stationary phase. However, the S-(-) enantiomers of saterinone and the internal standard were unresolved, as were the R-(+) enantiomers of both substances. Therefore, the two fractions were collected and each was separately resolved on an achiral Polyencap A reversed-phase column and quantified. The detection limit was 0.5 ng/ml of enantiomer, allowing the determination of plasma levels up to 36 h after oral administration of 90, 150 and 180 mg of saterinone to twelve subjects.