分子动力学和丙氨酸变异研究MDM2与抑制剂P4的结合模式

抑制p53-MDM2相互作用已经成为癌症治疗的新途径.采用分子动力学模拟和MM-PBSA(molecular mechanics-Possion-Boltzmann surface area)方法研究了肽类抑制剂P4与MDM2的结合模式.研究表明P4与MDMD2疏水性裂缝的范德华作用是抑制剂结合的主导力量。采用丙氨酸变异计算研究了P4与MDM2的作用热区.结果表明残基Lys51,Leu54,Leu57,Ile61,Met62,Tyr67,Gln72,His73,Val93,His96和Ile99的丙氨酸变异导致了范德华作用的降低,而对极性相互作用几乎没有产生影响,同时也证明这些残基处于P4与MDM2作用表面的热区,对抑制剂的结合有重要贡献,这能为抗癌药物的设计提供理论上的指导.     

MDM2与抑制剂PDIQ作用机制的结合自由能计算研究

近年来p53-MDM2相互作用已成为抗癌药物设计的重要靶标.本工作采用分子动力学模拟和结合自由能计算研究抑制剂PDIQ与MDM2的结合模式.结果显示范德瓦尔斯作用是抑制剂结合的主体力量.基于残基的自由能分解计算结果表明CH-CH,CH-π和π-π相互作用驱动了抑制剂与MDM2的结合.这一研究可为抗癌药物的设计提供一定的理论指导.     

分子动力学研究抑制剂APV与HIV-1蛋白酶的作用机制

采用分子动力学模拟和结合自由能计算研究了抑制剂APV与HIV-1蛋白酶的作用机制. 研究结果表明范德瓦尔斯作用主控了APV与HIV-1蛋白酶的结合. 采用基于残基的自由能分解方法计算了抑制剂-残基相互作用,结果表明9个残基Gly27、Ile32、Val47、Ile50、Ile84、Ala28′、Gly49′、Ile50′和Arg87′与APV产生了大于1.0 kcal/mol的强相互作用,而且证明CH-π,CH-O相互作用和极性作用是其结合的主要形式. 期待该结果可以为以HIV-1蛋白酶为靶标的抗艾滋病药物设计提供理论上的指导.     

分子动力学研究抑制剂APV与HIV-1蛋白酶的作用机制

采用分子动力学模拟和结合自由能计算研究了抑制剂APV与HIV-1蛋白酶的作用机制. 研究结果表明范德瓦尔斯作用主控了APV与HIV-1蛋白酶的结合. 采用基于残基的自由能分解方法计算了抑制剂-残基相互作用,结果表明9个残基Gly27、Ile32、Val47、Ile50、Ile84、Ala28′、Gly49′、Ile50′和Arg87′与APV产生了大于1.0 kcal/mol的强相互作用,而且证明CH-π,CH-O相互作用和极性作用是其结合的主要形式. 期待该结果可以为以HIV-1蛋白酶为靶标的抗艾滋病药物设计提供理论上的指导.     

抑制剂8Q9和8QC与bromodomain结构域蛋白4作用机理的分子动力学研究

Bromodomain结构域蛋白4（bromodomain-containing protein 4,BRD4）已成为治疗多种疾病药物设计的重要靶标. 最近在实验上发现了几种有效的靶向BRD4的抑制剂,但具体的抑制机理尚不清楚．此工作采用分子动力学模拟,动态相关性分析和结合自由能计算研究抑制剂8Q9和8QC与BRD4(1)的结合模式．分子动力学分析表明抑制剂结合对BRD4(1)的结构柔性产生重大影响．同时动态相关性分析进一步表明抑制剂结合极大地改变了BRD4(1)的运动模式．结合自由能计算结果表明范德华相互作用是抑制剂与BRD4(1)结合的主要驱动力．采用基于残基的自由能分解方法评估了分离残基对抑制剂结合的贡献,数据表明氢键相互作用和疏水相互作用是影响抑制剂与BRD4(1)结合的关键因素．本研究有望为设计和开发靶向BRD4的抑制剂提供有意义的理论指导．     

分子动力学研究抑制剂APV与HIV-1蛋白酶的作用机制

采用分子动力学模拟和结合自由能计算研究了抑制剂APV与HIV-1蛋白酶的作用机制.研究结果表明范德瓦尔斯作用主控了APV与HIV-1蛋白酶的结合.采用基于残基的自由能分解方法计算了抑制剂-残基相互作用,结果表明9个残基Gly27、Ile32、Val47、Ile50、Ile84、Ala28'、Gly49'、Ile50'和Arg87'与APV产生了大于1.0 kcal/mol的强相互作用,而且证明CH-π,CH-O相互作用和极性作用是其结合的主要形式.期待该结果可以为以HIV-1蛋白酶为靶标的抗艾滋病药物设计提供理论上的指导.     

分子动力学和丙氨酸变异研究MDM2与抑制剂P4的结合模式

抑制p53-MDM2相互作用已经成为癌症治疗的新途径. 采用分子动力学模拟和MM-PBSA(molecular mechanics-Possion-Boltzmann surface area)方法研究了肽类抑制剂P4与MDM2的结合模式. 研究表明P4与MDMD2疏水性裂缝的范德华作用是抑制剂结合的主导力量。采用丙氨酸变异计算研究了P4与MDM2的作用热区. 结果表明残基Lys51, Leu54, Leu57, Ile61, Met62, Tyr67, Gln72, His73, Val93, His96和Ile99的丙氨酸变异导致了范德华作用的降低, 而对极性相互作用几乎没有产生影响, 同时也证明这些残基处于P4与MDM2作用表面的热区, 对抑制剂的结合有重要贡献, 这能为抗癌药物的设计提供理论上的指导. 关键词：分子动力学; 丙氨酸变异; MM-PBSA; p53-MDM2相互作用     

抑制剂Benzamidine与胰岛素作用机制的分子动力学和结合自由能计算研究

氢键和极性相互作用在抑制剂-蛋白结合专一性识别过程中起到重要作用.抑制剂Benzamidine(BEN)与胰岛素trypsin相互作用机制的阐明有助于胰岛素高效抑制剂的研发.本文采用分子动力学模拟和MM-PBSA(molecular mechanics-Poisson Boltzmann surface area)从原子层次上研究BEN与胰岛素的结合模式.结果表明抑制剂BEN的脒基不仅与Asp189的羰基产生静电相互作用,而且与残基Ser190和Gly214形成氢键相互作用.基于残基能量分解的计算表明抑制剂的苯基与残基His58,Cys191,Gln192,Trp211,Gly212和Cys215形成有利于抑制剂结合的疏水性相互作用.期望当前的研究能为胰岛素有效抑制剂的研发提供重要的理论指导.     

抑制剂Benzamidine与胰岛素作用机制的分子动力学和结合自由能计算研究

氢键和极性相互作用在抑制剂-蛋白结合专一性识别过程中起到重要作用. 抑制剂Benzamidine(BEN)与胰岛素trypsin相互作用机制的阐明有助于胰岛素高效抑制剂的研发.本文采用分子动力学模拟和MM-PBSA(molecular mechanics-Poisson Boltzmann surface area)从原子层次上研究BEN与胰岛素的结合模式.结果表明抑制剂BEN的脒基不仅与Asp189的羰基产生静电相互作用，而且与残基Ser190和Gly214形成氢键相互作用.基于残基能量分解的计算表明抑制剂的苯基与残基His58, Cys191, Gln192, Trp211, Gly212和Cys215形成有利于抑制剂结合的疏水性相互作用.期望当前的研究能为胰岛素有效抑制剂的研发提供重要的理论指导.     

抑制剂8CA与脂肪细胞脂肪酸结合蛋白(A-FABP)结合模式的分子动力学研究

摘要：脂肪细胞脂肪酸结合蛋白A-FABP(Adipocyte fatty-acid binding protein)是治疗脂质调节生物过程相关疾病的重要靶标. 分子动力学模拟和MM-PBSA方法被采用研究抑制剂8CA与A-FABP结合模式. 研究结果表明静电相互作用和范德华作用驱动了抑制剂8CA与A-FABP的结合。基于残基的能量分解表明抑制剂8CA与R126间的极性相互作用为抑制剂与A-FABP的结合提供了重要贡献. 该残基与8CA的相互作用较好地稳定了抑制剂与A-FABP复合物的稳定性. 我们期望这个研究能为治疗炎症、动脉硬化和代谢病药物设计提供一定的理论指导。     

Protonation state and free energy calculation of HIV-1 protease–inhibitor complex based on electrostatic polarisation effect

The protonation states of catalytic Asp25/25′ residues remarkably affect the binding mechanism of the HIV-1 protease–inhibitor complex. Here we report a molecular dynamics simulation study, which includes electrostatic polarisation effect, to investigate the influence of Asp25/25′ protonation states upon the binding free energy of the HIV-1 protease and a C₂-symmetric inhibitor. Good agreements are obtained on inhibitor structure, hydrogen bond network, and binding free energy between our theoretical calculations and the experimental data. The calculations show that the Asp25 residue is deprotonated, and the Asp25′ residue is protonated. Our results reveal that the Asp25/25′ residues can have different protonation states when binding to different inhibitors although the protease and the inhibitors have the same symmetry. This study offers some insights into understanding the protonation state of HIV-1 protease–inhibitor complex, which could be helpful in designing new inhibitor molecules.     

苯并咪唑/苯并噻唑类T315I突变型Abl抑制剂的结合机理和分子设计

Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T315I mutant, makes the search for new Abl T315I inhibitors a very interesting challenge in medicinal chemistry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T315I. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T315I activities were designed and presented to experimenters for reference.     

Type II c-Met inhibitors: molecular insight into crucial interactions for effective inhibition

The c-Met tyrosine kinase plays an important role in human cancers. Preclinical studies demonstrated that c-Met is over-expressed, mutated and amplified in a variety of human tumor types and design of more potent c-Met inhibitors is a priority. In this study, 14 molecular dynamics simulations of potent type II c-Met inhibitors were run to resolve the critical interactions responsible for high affinity of ligands towards c-Met considering the essential flexibility of protein–ligand interactions. Residues Phe1223 and Tyr1159, involved in pi-pi interactions were recognized as the most effective residues in the ligand binding in terms of binding free energies. Hydrogen bond interaction with Met1160 was also found necessary for effective type II ligand binding to c-Met.

Graphic abstract

     

Estimation of Metformin Drug for the Diabetes Patients by Simple,Quick and Cheap Techniques within the Formation of Colored Charge Transfer Complexes

Metformin (Met) is a drug developed for the treatment of patients with type Ⅱ diabetes. Recently, Met estimation in pharmaceutical formulations and human fluids has gained a growing interest. To extend requisite data that can be used to assessment of Met quantitatively based on charge-transfer (CT) complexation, the present study describes the synthesis and characterization of CT complexes that formed between drug Met and the organic π-acceptors picric acid (PA), chloranilic acid (CLA), chloranil (CHL), 7,7’,8,8’-tetracyanoquinodimethane (TCNQ), and dichlorodicyanobenzoquinone (DDQ). The properties of the formed CT complexes were investigated by elemental, spectral (UV-visible, IR, and Raman spectroscopies), thermal (TG) and morphological (SEM) studies. IR results indicated that the complexation of Met with either PA or CLA acceptors occurs through proton transfer interaction, whereas its complexation with CHL, TCNQ, or DDQ acceptors occurs through n→π* interaction.     

Dynamics of Trp Residues in Crystals of Human α1-Acid Glycoprotein (Orosomucoid) Followed by Red-Edge Excitation Spectra

The present work reports for the first time the development of a method that allowed us to obtain crystals of orosomucoid complexed to progesterone. Then we investigated the dynamics of the microenvironments of the two buried Trp residues in the crystals of protein, by the red-edge excitation spectra method. The fluorescence excitation spectrum of the crystals is characteristic of that known for Trp residues (_max = 290 nm and bandwidth = 38 ± 1 nm), indicating that the Trp residues are responsible for the fluorescence of the protein in the crystals. The position of the maximum and the bandwidth of the steady-state emission spectrum of the crystals (331 ± 1 and 43 ± 1 nm, respectively) are equal to those obtained in aqueous buffer for the orosomucoid–progesterone complex (330 ± 1 and 43 ± 1 nm) (_ex, 295 nm). Thus, the fluorescence of the crystals occurs from the Trp residues buried in the protein core. The red-edge excitation spectra studies indicate that the Trp residues are surrounded by microenvironments that display motions, a result identical to that observed in solution. Thus, the crystallization process does not modify the structure or the dynamics of orosomucoid core. The fluorescence intensities depend on the angular orientation of the crystals with respect to the polarization of the incident beam. The general feature of this dependence is identical at the three excitation wavelengths used (295, 300, and 305 nm). Our results confirm the fact that the local structure and dynamics are the key for any interpretation of tryptophan fluorescence parameters of orosomucoid.     

Comparison of thermally detected optical absorption and electromodulation spectra of GaAs/AlGaAs quantum wells

We report for the first time a comparative study of GaAs/AlGaAs quantum well (QW) spectra obtained by thermally detected optical absorption (TD-OA) and photo- (PR) and electroreflectance (ER) experiments, respectively. The excitonic transition energies, obtained at low temperature with these methods, agree within 1 meV. It is demonstrated, using samples with different AlGaAs overlayer thicknesses, that the shape of the TD-OA response is strongly influenced by interference effects for QW's grown on absorbing substrates. A complete PR lineshape analysis yields phase angles for all transitions, whose differences can be attributed to the change of the AlGaAs front barrier thicknesses. ER investigations following successive top layer removal confirm this interpretation.     

无杂质空位扩散法造成InGaAsP/InP多量子阱结构带隙蓝移规律的研究

采用光荧光谱(PL)和光调制反射谱(PR)的方法,研究了由Si₃N₄、SiO₂电介质盖层引起的无杂质空位(IFVD)诱导的InGaAsP四元化合物半导体多量子阱(MQWs)结构的带隙蓝移。实验中Si₃N₄、SiO₂作为电介质盖层,用来产生空位,再经过快速热退火处理(RTA)。实验结果表明:多量子阱结构带隙蓝移和退火温度、复合盖层的组合有关。带隙蓝移随退火温度的升高而加大。InP、Si₃N₄复合盖层产生的带隙蓝移量大于InP、SiO₂复合盖层。而InGaAs、SiO₂复合盖层产生的带隙蓝移量则大于InGaAs、Si₃N₄复合盖层。同时,光调制反射谱的测试结果与光荧光测试的结果基本一致,因此,PR谱是用于测试带隙变化的另一种方法。     

生物医学核磁共振中的模式识别方法

模式识别(PR)是把具体事物进行正确归类的科学,它能解决许多对复杂体系的认识问题. 生物医学核磁共振波谱(NMR)的理解和分析便是其中一种. 在受到病理或者其他刺激后,生物体内的代谢物水平会发生变化,这种变化可以通过液体高分辨核磁共振的手段来观察. 模式识别把这种认识进一步深化,不仅可以将正常状态与病理状态区分开,还能找到是哪些生化指纹导致两种状态的差异,为生理、病理和药理等研究,以及临床诊断提供依据. 模式识别与生物核磁共振波谱的结合,已经发展成为代谢组学研究的关键技术,甚至被称为基于核磁共振的代谢组学. 主要讨论适用于生物医学核磁共振中的模式识别方法及其最新进展.