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1.
本文采用分子对接法研究了24个5,6-二氢-2-吡喃酮衍生物与HIV-1蛋白酶的相互作用,并采用三维定量构效关系(3D-QSAR)研究了药物分子化学结构和生物活性之间的关系.最终得到模型的复相关系数(R_(cum)~2)为0.961、留一法交互校验复相关系数(Q_(cv)~2)为0.897,外部交互验证复相关系数(Q_(ext)~2)为0.880,从结果可以看出三维定量构效关系对化合物的抗艾滋病活性具有比较好的预测能力.然后通过分子对接研究了配体小分子和HIV-1蛋白酶活性氨基酸残基之间的结合模式,这些信息对于以后设计合成新的抗艾滋病药物具有一定的指导作用.  相似文献   

2.
HIV蛋白酶是一类用于治疗艾滋病具有潜在价值的关键酶,很多此类酶的抑制剂已经上市.一系列由AHPBA分子的基本骨架进行改造并合成的25个α-羟基β-氨基酸类似物对于HIV蛋白酶具有很高的活性和选择性.我们筛选合适的描述子建立一个二维定量构效关系的模型,模型的均方根误差RMSE=0.09823、相关性系数R=0.97461、F值=30.763、交叉验证的相关系数RCV=0.7071、交叉验证的预测误差平方PRESS=0.588,该模型为HIV蛋白酶抑制剂修饰和设计提供了比较可靠的预测.并且根据“变形钥匙”理论,分别用“杂化肽键”Ψ[CH2NH]、Ψ[CF2NH]、Ψ[COCF2]、替换掉这组类似物中易水解的肽键-CO=NH-,使得这个共轭π键就变成一个较强的单键,变得不易被HIV蛋白酶所水解,从而得到抗AIDS的有效的抑制剂.然后通过原子电荷分布对比、分子对接等方法检验修饰的可能性和合理性.预先设想都在计算结果中得到验证,并且用QSAR模型预测了修饰后分子的活性.  相似文献   

3.
A3G(apolipoprotin B mRNA-editing catalytic polypeptide 3 protein G)是一种天然抗病毒活性的胞嘧啶脱氨基酶,具有广谱的抗病毒作用,属于人体固有的免疫蛋白分子. 在HIV病毒复制过程中,A3G蛋白能进入新生成的病毒颗粒内部,诱导病毒cDNA胞嘧啶脱氨基化变为尿嘧啶,阻断病毒复制,从而导致病毒活性丧失. 最近几年,许多实验室以NMR技术和X射线衍射技术为基础,开展了一系列A3G蛋白的结构生物学和脱氨基化反应动态过程的研究,取得了具有重要意义的研究进展,为后期的研究工作提供了很好的新思路. 通过对这些工作进行总结,以期为我国艾滋病、乙肝病毒的防治,及相关药物分子的设计提供新的借鉴.  相似文献   

4.
 亚洲和欧洲的实验室通力协作,利用科学电子化整合计划(EnableGridforE-science,EGEE)网格系统分析了30万种可能对抗禽流感病毒H5N1的药物成分,目的是寻找有效抑制禽流感病毒表面酶(即神经氨酸酶N1亚型)活性的成分。用网格系统确定最适于进行生物试验的成分,将加快药物的研制速度。这次计算机模拟开发新药的一个挑战,是确定能够与病毒活性位点对接以抑制其活动的分子。在4月的4个星期里,科学家利用2000台计算机(相当于1台计算机100年的运算量)研究了30万种对抗A型流感病毒神经氨酸酶8种结构的成分的分子对接,关系数据库中产生并存储了数据总量为600GB的6万多个文件。  相似文献   

5.
采用分子对接和分子动力学模拟的方法,研究了抗氧化三肽SHW与Keap1蛋白的相互作用,揭示了非竞争性结合的分子机制.分别位于Keap1的P1和P5活性口袋的Keap1蛋白关键残基ARG-415和TYR-525通过与SHW形成氢键来增强结合强度且对结合能有突出贡献. SHW的吲哚基团是与TYR-334、TYR-525和TYR-572形成疏水作用的关键,促进与P5口袋的结合.研究结果揭示了SHW通过Keap1-Nrf2信号通路作用于活性口袋的分子机制,为抗氧化剂的开发提供理论依据.  相似文献   

6.
用分子对接方法 (Docking)研究了HIV 1整合酶与其抑制剂金精三羧酸的结合过程 .为弄清金属离子在结合中所起的作用 ,选择含有一个Mg+ 2 或不含Mg+ 2 的两种不同的整合酶受体分别与金精三羧酸对接 .结果表明 ,Mg+ 2 对稳定配体与受体的结合起了重要作用 .金精三羧酸配体与含有一个金属Mg+ 2 的整合酶受体对接 ,最优结合自由能为 - 4 5 .19kJ/mol.当Mg+ 2 失去后 ,整合酶的活性中心构象将发生变化 ,使金精三羧酸抑制剂与整合酶的结合自由能 (- 2 4 .35kJ/mol)明显增加 .预测了未知的HIV 1整合酶与其抑制剂金精三羧酸的复合物结构 ,并可对基于结构的抗HIV 1整合酶的药物设计提供重要信息  相似文献   

7.
亚洲和欧洲的实验室通力协作,利用科学电子化整合计划(EnableGridforE-science,EGEE)网格系统分析了30万种可能对抗禽流感病毒H5N1的药物成分,目的是寻找有效抑制禽流感病毒表面酶(即神经氨酸酶N1亚型)活性的成分。用网格系统确定最适于进行生物试验的成分,将加快药物的研制速度。这次计算机模拟开发新药的一个挑战,是确定能够与病毒活性位点对接以抑制其活动的分子。在4月的4个星期里,科学家利用2000台计算机(相当于1台计算机100年的运算量)研究了30万种对抗A型流感病毒神经氨酸酶8种结构的成分的分子对接,关系数据库中产生并存储了数…  相似文献   

8.
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.  相似文献   

9.
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.  相似文献   

10.
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.  相似文献   

11.
12.
Qi-Yuan Cheng 《中国物理 B》2022,31(10):103301-103301
The field-free alignment of molecule ClCN is investigated by using a terahertz few-cycle pulse (THz FCP) based on the time-dependent density matrix theory. It is shown that a high degree of molecular alignment can be obtained by changing the matching number of the THz FCPs in the adiabatic regime and the non-adiabatic regime. The matching number can affect both the maximum value of the alignment and the time at which it is achieved. It is also found that a higher degree of alignment can be achieved by using the THz FCP at lower intensity and there exists an optimal threshold of molecular alignment with the increase of the field amplitude. Also found is the frequency sensitive region in which the degree of maximum alignment can be enhanced greatly by modulating the center frequencies of different THz FCPs. The investigation demonstrates that comparing with a THz single-cycle pulse, a better result of the field-free alignment can be created by a THz FCP at a constant rotational temperature of molecule.  相似文献   

13.
14.
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.  相似文献   

15.
From density-functional-theory based methods, we calculate the vibrational spectrum of the Mn(12)O(12)(COOH)(16)(H(2)O)(4) molecular magnet. Calculated infrared intensities are in accord with experimental studies. There have been no ab initio attempts at determining which interactions account for the fourth-order anisotropy. We show that vibrationally induced distortions of the molecule contribute to the fourth-order anisotropy Hamiltonian and that the magnitude and sign of the effect (-6.2 K) is in good agreement with all experiments. Vibrationally induced tunnel splittings in isotopically pure and natural samples are predicted.  相似文献   

16.
Azilsartan, a new antihypertensive drug, has effects on the sympathetic nervous system and expression of genes. The interaction of Azilsartan with DNA was investigated using molecular docking and multi-spectral techniques. Molecular docking revealed that Azilsartan could interact with DNA via groove binding from a theoretical perspective. Time-resolved fluorescence measurements indicated that the quenching mechanism was static, and further analysis of quenching data demonstrated that the binding was spontaneous and mainly driven by hydrophobic forces. The results of interaction with denatured DNA, viscosity, infrared spectroscopy, and circular dichroism showed that Azilsartan could bind to DNA through groove binding, which was consistent with docking analyses.  相似文献   

17.
In this study, the binding mode of nobiletin (NOB) with pepsin was investigated by spectroscopic and molecular docking methods. NOB can interact with pepsin to form a NOB-pepsin complex. The binding constant, number of binding sites and thermodynamic parameters were measured, which indicated that NOB could spontaneously bind with pepsin through hydrophobic and electrostatic forces with one binding site. Molecular docking results revealed that NOB bound into the pepsin cavity. Synchronous and three-dimensional fluorescence spectra results provide data concerning conformational and some micro-environmental changes of pepsin. Furthermore, the binding of NOB can inhibit pepsin activity in vitro. The present study provides direct evidence at a molecular level to show that NOB could induce changes in the enzyme pepsin structure and function.  相似文献   

18.
Uniform and defect-free homeotropic (HMT) alignment of ferroelectric liquid crystals (FLC) cells have been successfully achieved by a non-contact technique, namely, magnetic field-assisted alignment; otherwise such alignment is difficult by conventional methods. Frequency-temperature dependent dielectric studies, confirm the presence of stable molecular relaxation around the short axis of FLC molecule, throughout SmC*-SmA* phases with minimum low-frequency fluctuations, known as Goldstone modes. The proposed non-contact alignment method, combined with FLC-based HMT configuration, would be much promising for integrated-optoelectronic devices, such as micro-mirror displays.  相似文献   

19.
In this study, the molecular interaction of silybin with hyaluronidase was investigated by spectroscopic methods and molecular docking. It was found that silybin had strong ability to quench the intrinsic fluorescence of hyaluronidase by a static quenching procedure. The binding constants were obtained at three temperatures (293, 298, and 310 K). The results of synchronous fluorescence and three-dimensional fluorescence and molecular docking showed that silybin bound into the hyaluronidase cavity site and the binding of silybin to hyaluronidase could induce micro-environmental and conformational changes in hyaluronidase, which resulted in the reduced hyaluronidase activity. The thermodynamic parameter analysis and molecular docking experiments revealed that all types of non-covalent interaction, including hydrogen bonding interaction, van der Waals forces, hydrophobic interaction, and electrostatic interaction were present in the binding process of silybin with hyaluronidase. The results obtained here will provide direct evidence at a molecular level to understand the mechanism of the inhibitory effect of silybin against hyaluronidase.  相似文献   

20.
利用O-GlcNAc 转移酶同UDP-GlcNAc复合物的晶体结构,针对其催化位点,对ZINC库中的7134792个分子和FOG库中的4287550个分子进行三轮(HTVS、SP、XP)虚拟筛选,结果发现具有更好类药性的FOG库中包含更多对接得分更低的小分子,且具有更多新颖的化学片段.ZINC库中具有较低对接得分的分子可分为2类,分别占据UDP-GlcNAc的UDP和GlcNAc的结合位置,在此基础上设计得到的分子具有更好的对接得分.证明FOG分子库具有产生更多对接得分更低的分子,所预测和设计的小分子化合物可以成为潜在的抑制剂药物分子.  相似文献   

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