人抑胃肽溶液构象的荧光光谱学研究

运用荧光光谱方法研究了用固相合成法得到的人抑胃肽（ＧＩＰ－４２）及其类似物的内源荧光特性，Ｉ＾－动态荧光淬火以及与ｂｉｓ－ＡＮＳ结合的荧光，结果表明：ＧＩＰ－４２在溶液中具有一定的构象，其Ｔｒｐ残基荧光被Ｉ＾－淬灭的结果表现为双相，淬灭常数分别为１１．５Ｌ／ｍｏｌ和１．２Ｌ／ｍｏｌ，ＧＩＰ－４２肽中有一疏水区能与探针ｂｉｓ－ＡＮＳ结合，在Ｎ－端７个残基除去后所得到的２５肽（ＧＩＰ－２５）分子中，Ｉ     

卡培他滨核磁共振现象研究

目的 研究卡培他滨在不同溶剂、不同温度下的核磁共振现象.方法 分别测定卡培他滨在不同极性的氘代溶剂(CDCI3、CD3OD和DMSO-d6)及不同温度(283、293、303、323、333 K)时的氢谱和碳谱.结果 卡培他滨在不同溶剂、不同温度下的NMR谱,特别是碳谱上,脱氧核苷和胞嘧啶环上的碳信号有明显差异.结论 卡培他滨在以CD3OD为溶剂,在较低温度时,其主要为单一构象结构,碳信号基本为一组信号.在此条件下测定其相应1D和2D谱,对其质子和碳信号进行了完整归属.     

苦豆子多糖溶液构象的研究

目的研究苦豆子多糖溶液的构象特征以及在不同因素影响下的溶液行为。方法采用碘–碘化钾反应观察苦豆子多糖链的分支情况和刚果红试验研究构象特征;采用圆二色谱(CD)法研究在不同浓度、温度和添加钙离子等条件下苦豆子多糖构象的变化。结果碘–碘化钾反应结果显示苦豆子多糖有较长的侧链和较多的分支;刚果红试验中苦豆子多糖具有多股螺旋结构;浓度、温度以及添加金属离子使苦豆子多糖溶液构象发生变化。结论通过碘–碘化钾反应、刚果红试验和圆二色谱法的结合可更加全面地了解苦豆子多糖溶液的构象。     

喜树碱构象的量子化学研究及其与晶体结构的比较

喜树碱类抗肿瘤药物是临床广泛使用的经典的作用于DNA拓扑异构酶Ⅰ的特异性抑制剂。已有的喜树碱构象研究结果彼此并不一至岙 采用可靠方法进行构象研究是阐明该药物作用模式的关键一环。本文在分子动力学搜寻喜树碱构象空间的基础上,采用量子化学的半经验AM1、PM3方法和ab initio的RHF/3-21G、RHF/6-31G方法对近似晶体结构构象的分子力学构象进行了系统优化。所得构象均采用密度泛函方法B3LYP/6-31G（d)进行单点能计算,并和喜树碱碘乙酸酯的晶体结构进行了比较。结果表明,ab initio方法得到的构象更接近晶体结构构象,而半分子内氢键,使E环内酯键反应性提高,可与TopoI-DNA共价复合物形成较好的相互作用。同时又使喜树碱易受溶剂水的影响而开环失去活性。     

喜树碱药效构象及分子内氢键对抗肿瘤活性的影响

喜树碱类抗肿瘤药物是临床广泛使用的DNA拓扑异构酶Ⅰ（topoisomerase Ⅰ,Topo Ⅰ）的特异性抑制剂。为从原子水平阐明喜树碱的作用模式,设计结构新,知性更高、毒性更低的TopoⅠ抑制剂,本研究采用ab initio方法RHF／3－21G对喜树碱分子构象空间进行了系统研究,并与半经验量化AM1、PM3方法比较,所得构象均采用密度泛函方法B3LYP／6－31G（d)计算单点能,并进行频率检查验证。结果发现,A型构象可恰好氢键,较B型构象能量更低,为喜树碱药效构象。喜树碱E环形成分子内氢键,能量约为29.31kJ/mol,这是该分子发挥药效的结构基础,同时使得它易于受溶剂水影响而裂解,生成无活性的羧酸盐形式。本研究还表明,喜树碱与TopoⅠ－DNA复合物作用,需破坏分子内氢键,能量补偿较大,提示设计更为高效的TopoⅠ抑制剂具有可能性。     

棉酚及其相关化合物的分子力学和分子图形学研究

本文运用分子力学和分子图形学这些研究有机和药物分子空间构象的有效方法,研究并阐明了具有抗男性生育活性的棉酚及其有关化合物的立体化学现象。     

雌激素受体和选择性雌激素受体调节剂相互作用的分子模拟

目的:研究一类高活性消旋化的雌激素受体调节剂与其受体间的相互作用机制.方法:分子力学优化的方法获得这类刚性的raloxifene类似物的活性构象,受体与配基间的相互作用能用分子对接程序计算.结果:化合物的R和S构型均可进入雌激素受体的结合腔.其羟基直接与受体氨基酸形成氢键,其酚环相当于雌激素的A环.活性最好的配基带有两个羟基,并已模拟雌激素A环为含16位羟基的酚环的S构型化合物.结论:消旋化对该类化合物的活性影响不大.羟基对于化合物在活性11袋中的取向及与受体的结合有着重要意义.     

构象型B细胞抗原表位的研究方法及进展

识别保护性B细胞抗原表位从而引发中和抗体产生和体液免疫,是特异性免疫反应的物质基础,因此,研究可被中和抗体识别的保护性B细胞抗原表位对促进基础免疫学发展、感染诊断、相关疫苗特别是多肽疫苗的研发、药物靶点筛选等具有积极意义.虽然此类表位多为构象型,研究难度较大,但随着免疫学和生物信息学技术的发展,已出现许多有效思路与方法.此文综述目前构象型B细胞抗原表位的研究方法及进展.     

利用傅里叶变换红外光谱法研究重组人粒细胞巨噬细胞集落刺激因子溶液中的构象

利用傅里叶变换红外光主普（FTIR）技术研究了重组人粒细胞——巨噬细胞集落刺激因子（rhGM-CSF)在重水（D2O）溶液中的二级结构，结果表明：20℃时rhGM-CSF含有35%α-螺施，32%β-折叠，11%转角和20%无规卷曲。     

电压门控型钾通道孔区的分子建模

目的：建立和验证电压门控型甸通病的结构模型，方法：（１）从实验和理论研究结果提以结构约束条件；（２）建立满足这些约束条件的初始结构模型，并进一步用限制性分了力学优化；（３）根据模型能否成功地解释通道功能分子机制和许多实验事实判断其合理性，结果：（１）建立了一个孔区模型，共中信号离列残基（对应Ｓｈａｋｅｒ４３９－４４６）以非周期性构象嵌入中并形成孔区比较窄的部分，而孔区域的其它残基构成孔外口；（２）     

菊淀粉型低聚糖类的^1HNMR及^13CNMR研究

本文应用二量子滤波＾１Ｈ－＾１Ｈ ＣＯＳＹ，＾１Ｈ－＾１３Ｃ ＣＯＳＹ及远程＾１Ｈ－＾１３Ｃ ＣＯＳＹ等二维核磁共振技术，结合与类似物的化学位移值比较，分析归属了菊淀粉型低聚糖（１￣４）的＾ＨＮＭＲ及＾１３ＣＮＭＲ信号。     

夏至矢车菊内酯的NMR研究

以一维核磁共振谱（１Ｈ－ＮＭＲ，１３Ｃ－ＮＭＲ，ＤＥＰＴ）和二维核磁共振谱（１Ｈ－１ＨＣＯＳＹ，ＨＭＱＣ，ＨＭＢＣ，ＮＯＥＳＹ）为主要手段研究了从祁州漏芦地上部位分离得到的夏至矢车菊内酯（Ⅰ）．确认了其结构，圆满地归属了其１Ｈ－ＮＭＲ和１３Ｃ－ＮＭＲ信号，并对其立体化学进行了研究     

Solution conformation of Endothelin-1 by 1H NMR,CD, and molecular modeling

The solution conformation of Endothelin-1, a recently discovered bicyclic, 21 amino acid peptide, has been examined by ¹H NMR in deuterated dimethylsulphoxide and circular dichroism in aqueous and organic solvents. A total of 158 NOES were detected, which were used as distance constraints in the distance geometry program DISGEO. Two families of structures were obtained, both characterized by a helix-like region extending from Lys⁹ to Cys¹⁵, but with opposite “handedness”. Circular dichroism studies of the peptide in both aqueous and trifluoroethanol solutions show a negative shoulder at 224 nm, characteristic of right-handed helices. Molecular dynamics and energy minimization yielded a solution structure for this new peptide compatible with all experimental observations.     

Conformation of dehydropeptides

Six model dipeptide methyl amides containing dehydroaminobutyric acid (Δ Abu) of the type Boc-X-δ^ZAbu-NHCH₃ and Box-X-δ^EAbu-NHCH₃, X = Ala, Val, Phe (Boc =tert-butoxycarbonyl), have been synthesized and their solution conformations explored using 300 MHz ¹H NMR and IR spectroscopy. Studies based on delineation of intramolecularly hydrogen bonded NH groups in CDCl₃ and (CD₃)₂SO revealed that none of the NH groups is appreciably solvent shielded. Difference NOE (Nuclear Overhauser Effect) studies have also failed to detect the presence of any discernible turn structure in these peptides. These studies indicate that the conformational preferences of peptides containing, α, β-dehydroaminobutyric acid are different from those of Δ^ZPhe and Δ^ZLeu. It appears that steric interactions due to the β-substituent in the dehydroamino acid moiety play an important role. Unlike Δ^ZPhe and Δ^ZLeu, which have relatively large β-substituents, phenyl and isopropyl, respectively, and stabilize a β-turn, the β-methyl group of Δ^ZAbu or Δ^EAbu is readily accommodated in extended conformation. Clearly, the size of β-substituent in dehydroamino acid crucially influences the conformational preferences. Thus, it may be possible to use different dehydroamino acids to introduce variable but definite constraints in synthetic peptides.     

A Solution Conformation Analysis of Forocidins I and Isoforocidins I Using NMR and Molecular Modeling

Pharmaceutical Research -     

Nuclear Magnetic Resonance and Infrared Spectroscopic Analysis of Nedocromil Hydrates

Purpose. Nedocromil sodium (NS), which is used in the treatment ofreversible obstructive airway diseases, such as asthma, has been foundto exist in the following solid phases: the heptahemihydrate, thetrihydrate, a monohydrate, an amorphous phase, which contains variableamounts of water, and a recently discovered methanol + water (MW)solvate. Our aim was to apply ¹³C solid-state nuclear magneticresonance (NMR) spectroscopy and solid-state Fourier transform infrared(FTIR) spectroscopy to the study of specific interactions in the varioussolid forms of NS. Methods. The ¹³ solid-state NMR and FTIR spectra of the varioussolid forms of NS were obtained and were related to the crystalstructures of NS, the conformations of the nedocromil anion, and theinteractions of the water molecules in these crystals. Results. The ¹³C solid-state NMR spectrum is sensitive to theconformation of the nedocromil anion, while the solid-state FTIR spectrumis sensitive to interactions of water molecules in the solid state. In NSmonohydrate, for which the crystal structure has not yet been solved,and in the amorphous phase, the information about the conformationsof the nedocromil anion and the interactions of the water moleculesare deduced from the ¹³C solid-state NMR spectra and solid-state FTIRspectra, respectively. Conclusions. ¹³C solid-state NMR spectroscopy and solid-state FTIRspectroscopy are shown to be powerful complementary tools forprobing the chemical environment of molecules in the solid state,specifically the conformation of the nedocromil anion and the interactions ofwater-molecules, respectively.     

Solution Conformations Shed Light on PROTAC Cell Permeability

Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.     

Conformation of Amiodarone · HC1: A Solution and Solid State 13C-NMR Study

The comparison of ¹³C-NMR spectra of Amiodarone · HC1 in different solvents with the CPMAS spectrum and the crystal structure shows that the molecule adopts a single twist conformation both in the solid-state and in solution in nonpolar solvents.     

Molecular Properties of Ibuprofen and Its Solid Dispersions with Eudragit RL100 Studied by Solid-State Nuclear Magnetic Resonance

Purpose The aim of this study was to investigate, at a molecular level, the structural and dynamic properties of the acidic and sodium salt forms of ibuprofen and their solid dispersions with Eudragit RL-100, obtained by two different preparation methods (physical mixtures and coevaporates), which may affect the release properties of these drugs in their dispersed forms.Methods ¹H and ¹³C high-resolution solid-state nuclear magnetic resonance techniques, including single-pulse excitation magic-angle spinning, cross-polarization magic-angle spinning, and other selective 1D spectra, as well as more advanced 2D techniques Frequency Switched Lee-Goldburg HETeronuclear CORrelation (FSLG-HETCOR) and Magic Angle Spinning -J- Heteronuclear Multiple-Quantum Coherence (MAS-J-HMQC) and relaxation time measurements were used.Results A full assignment of ¹³C resonances and precise ¹H chemical shift values were achieved for the first time for the two forms of ibuprofen that showed very different interconformational dynamic behavior; drug–polymer interactions were observed and characterized in the coevaporates of the two forms but were much stronger for the acidic form.Conclusions A combined analysis of several high-resolution solid-state nuclear magnetic resonance experiments allowed the investigation of the structural and dynamic properties of the pure drugs and of the solid dispersions with the polymer, as well as of the degree of mixing between drug and polymer and of the chemical nature of their interaction. Such information could be related to the in vitro drug release profiles observed for the tested coevaporates.     

Conformation of MeAla6-cyclosporin A by NMR

MeAla6-cyclosporin A (MeAla6-CsA) is a unique CsA analog that shows weak immunosuppressive activity and yet binds strongly to the proposed cytosolic protein receptor, cyclophilin (CyP). Preliminary ¹H NMR data showed significant chemical shift differences between spectra of MeAla6-CsA and CsA, suggesting different preferred conformations. A more detailed study, however, revealed that the backbone conformations of the two molecules are essentially identical, and that the differences can be accounted for, principally, by the sidechain motions of the MeBmt-1, MeLeu-9, and -10 residues. ROE and coupling constant data show that in MeAla6-CsA, the preferred χ₁ rotamers for MeLeu-9 and -10 are + 180° (T), whereas in CsA there is a more even distribution of rotamer populations for MeLeu-10, and a preferred – 60° (G^?) χ₁ rotamer for MeLeu-9. Similar data argue that the sidechain of MeBmt-1 is more restricted in its motion in MeAla-CsA than in CsA. Temperature studies suggest that these preferred rotamers for MeAla6-CsA may increase the stability of the hydrogen bond between NH(7) and CO(II), but prevent particular residues, especially the essential MeBmt-I sidechain, from adopting orientations required to elicit immunosuppressive activity. The significant changes observed in the preferred orientations for the side-chains of the MeBmt-1, MeLeu-9, and MeLeu-10 residues in MeAla6-CsA argue that the particular orientations which they assume in CsA are not essential for cyclophilin binding.