寡聚酰胺为探针的电化学DNA生物传感器

DNA分子中的碱基对可以长程传递电荷, DNA分子中的碱基π堆积结构为电荷的长程传递提供了良好的通道. 电荷在DNA分子中的传递受碱基序列的影响, 利用这种性质可以构建DNA碱基错配检测的电化学传感器. 寡聚酰胺能和DNA以小沟绑定方式高亲和力地结合, 并且具有序列识别功能, 本文以带有硝基官能团的寡聚酰胺分子为电化学探针, 设计了电化学DNA生物传感器. 结果显示, 寡聚酰胺与DNA修饰电极作用后, 电化学响应显著增强, 并且可以作为检测DNA碱基错配的电化学探针分子.     

新型的DNA切割试剂制备与应用

将具有DNA选择性识别的小分子与具有DNA切割活性的小分子缀合,合成对DNA具有定点切割效果的试剂是化学生物学研究领域具有挑战性的研究之一,它为化学、药学和生物学在生命科学中的相互渗透开辟了又一个广阔的空间.设计了具有切割系统和识别系统的定点切割试剂,识别系统由寡聚酰胺组成,含有N-甲基吡咯的寡聚酰胺能够穿透细胞膜与特定的碱基序列高亲和力地结合,并控制基因表达,是一类十分重要的化学物质;切割系统由大环多胺和它的金属配合物构成,大环多胺的金属配合物可作为仿酶催化剂.化合物1的锌配合物对pBR322DNA的切割见下图,此结果为进一步研究DNA特异识别及切割分子提供一个良好的基础.     

由氢键引导的、经强制可控折叠形成的含孔折叠分子结构

受蛋白折叠现象的启发,发展出了一类基于芳香寡聚酰胺的分子折叠体系。研究发现苯环单元带有邻位烷氧基的芳酰胺寡聚体,可经由高度稳定的分子内3中心氢键,使原本可自由转动的酰胺和芳环间的单键受到限制,导致整个分子骨架的平面及刚性化,并折叠成为向一侧弯曲的构象。不同长度的寡聚酰胺分子,在3中心氢键的引导与强制下折叠形成含有内部孔穴的弯月形或螺旋结构。进一步研究表明这些分子所含的内孔是非常稳定的。由于此类折叠分子骨架的刚性及其构象的稳定性,其内孔尺度大小可通过引入不同）间位及对位）取代的苯环单元,以调节寡聚酰胺骨架的弯曲度,从而加以精确调控。基于此策略,制备了中心孔径从9到30的弯月形或螺旋结构。稍后的研究发现,利用分子内3中心氢键的引导与强制作用,可实现具有同类芳酰胺骨架的刚性大环的一步高效合成。主要简介在芳香寡聚酰胺的强制可控折叠,及其应用于弯月形、螺旋折叠分子以及大环分子的制备方面的研究。     

含对溴苯基的新型DNA切割剂的合成及活性研究

人工合成的光引发活性 DNA切割剂在化学、生物学和医药等领域中具有重要的学术意义和潜在的应用价值 [1,2 ] .DNA切割分子可以在光的引发下切割 DNA,它的优点在于对体系从时间和空间上进行控制 .目前已经成功地合成出芳香族卤化物、醌类、金属络合物、 C60 衍生物等多种光引发活性 DNA切割剂 .将 DNA识别分子与光切割分子相连 ,则可以合成具有识别功能的光引发活性 DNA切割分子 .卤代苯基是一类重要的光活性基团 ,在紫外光引发下 ,生成苯基自由基切割 DNA[3 ] .偏端霉素是含有 3个吡咯环的寡聚酰胺 ,它是一种天然的抗肿瘤抗生素 ,…     

喜树碱类抗肿瘤药物作用模式的柔性分子对接研究

研究采用柔性分子对接技术，将15个喜树碱类化合物对接到拓扑异构酶I (Topo I)-DNA切割复合物中，从原子水平和分子力场角度阐明了喜树碱类抗肿瘤药 物与DNA，Topo I的相互作用机制。研究发现，喜树碱分子插入Topp I-DNA复合物 的切割位点，并与Asn722，Asp533，Lys532和Lys720形成氢键作用网络。定量构效 关系研究进一步表明喜树碱分子可以与Topo I-DNA切割复合物形成电荷迁移作用。 该对接模型系统解释了喜树碱类化合物的构效关系、定点突变等诸多实验事实，为 下一步设计、合成新型高效的喜树碱类衍生物打下了坚实基础。     

金属配合物-寡聚核苷酸定位断裂剂研究进展

核酸切割试剂与寡聚核苷酸(ODN)偶联制得的人工核酸酶能在特定位点断裂DNA或RNA,为人工核酸酶的分子设计提供了一种新方法.本文综述了金属配合物-ODN识别切割试剂的偶联方式及其与靶分子的作用机制,并指出了今后的研究方向.     

密度泛函理论研究聚烯烃催化剂取代基电子效应与催化活性的关系

 采用密度泛函 BP/DNP 优化了五组 (每组化合物具有相同的框架结构和不同电子效应的取代基) 共 18 个最受关注的烯烃配位聚合催化剂, 分别计算了每个化合物中心金属上的 Hirshfeld、Mulliken 和 QEq 电荷, 中心金属的 Fukui 指数以及化合物的 HOMO 和 LUMO 能量值, 然后将这些结构参数和配合物催化乙烯聚合的活性相关联. 结果发现, 中心金属的 QEq 电荷能正确反映取代基的电子效应, 且与化合物的 HOMO 以及 LUMO 能量值与催化活性之间有良好的相关性, 可用来预测催化剂活性; 而 Hirshfeld 和 Mulliken 电荷不能正确反映取代基的电子效应, 不适合计算这些化合物的中心金属电荷. 中心金属的 Fukui 指数受取代基电子效应影响较小, 和催化剂活性之间的相关性不明显.     

寡聚酰胺PyPyPybDp与DNA相互作用的荧光动力学

通过稳态吸收光谱、荧光光谱和时间分辨荧光光谱对寡聚酰胺分子PyPyPybDp(简称PPP)的光物理性质进行了详细研究. 发现PPP的激发态性质受溶剂环境影响较大, 在TKMC缓冲液中, PPP有较弱的荧光, 其荧光寿命为16 ps; 随着溶剂极性逐渐降低, 荧光光谱蓝移, 荧光强度增加, 相应荧光寿命增长. 通过对PPP与DNA双螺旋分子相互作用的荧光动力学研究表明, PPP与DNA相互作用后, 荧光强度增强, 荧光寿命从16 ps增加到32 ps, 证实了存在PPP与双螺旋DNA的结合相互作用.     

寡聚酰胺PyPyPyβDp与DNA相互作用的荧光动力学

通过稳态吸收光谱、荧光光谱和时间分辨荧光光谱对寡聚酰胺分子PyPyPy(Dp(简称PPP)的光物理性质进行了详细研究. 发现PPP的激发态性质受溶剂环境影响较大, 在TKMC缓冲液中, PPP有较弱的荧光, 其荧光寿命为16 ps; 随着溶剂极性逐渐降低, 荧光光谱蓝移, 荧光强度增加, 相应荧光寿命增长. 通过对PPP与DNA双螺旋分子相互作用的荧光动力学研究表明, PPP与DNA相互作用后, 荧光强度增强, 荧光寿命从16 ps增加到32 ps, 证实了存在PPP与双螺旋DNA的结合相互作用.     

两亲性大环多胺La(III)配合物的合成、表征及催化质粒DNA水解的研究

近年来,人工核酸切割试剂的研究一直是化学生物学、生物化学和分子生物学中最为活跃的前沿领域之一。最近的研究结果表明大环多胺金属配合物在磷酸二酯水解方面表现出独特的催化性能,能作为化学核酸酶有效的催化DNA和RNA的磷酸二酯键的水解[1-2]。尤其是电荷较高的金属阳离子形     

Evaluations of AMBER force field parameters by MINA approach for copper-based nucleases

We describe the development of the AMBER force field parameters for 46 nucleases involving most kinds of copper nucleases with high DNA affinities and specificities by MINA approach that could evaluate accurate force constants for batch bonds/angles on the basis of energies of three adjacent lengths/angles geometries. The molecular mechanics (MM) and molecular dynamic simulations on adducts of the 21 representative copper-based nucleases with DNA are in excellent agreement with those of experimental results. Furthermore, to validate the evaluated parameters, the studied structures performed frequency analysis together with normal mode calculations in quantum mechanics and MM calculations. The force field parameters evaluated in this work provide an extension of AMBER force field, and the results of molecular dynamics simulations of adduct of copper nuclease and duplex DNA illustrate the potential utility of these parameters.     

An anchor-dependent molecular docking process for docking small flexible molecules into rigid protein receptors

A molecular docking method designated as ADDock, anchor- dependent molecular docking process for docking small flexible molecules into rigid protein receptors, is presented in this article. ADDock makes the bond connection lists for atoms based on anchors chosen for building molecular structures for docking small flexible molecules or ligands into rigid active sites of protein receptors. ADDock employs an extended version of piecewise linear potential for scoring the docked structures. Since no translational motion for small molecules is implemented during the docking process, ADDock searches the best docking result by systematically changing the anchors chosen, which are usually the single-edge connected nodes or terminal hydrogen atoms of ligands. ADDock takes intact ligand structures generated during the docking process for computing the docked scores; therefore, no energy minimization is required in the evaluation phase of docking. The docking accuracy by ADDock for 92 receptor-ligand complexes docked is 91.3%. All these complexes have been docked by other groups using other docking methods. The receptor-ligand steric interaction energies computed by ADDock for some sets of active and inactive compounds selected and docked into the same receptor active sites are apparently separated. These results show that based on the steric interaction energies computed between the docked structures and receptor active sites, ADDock is able to separate active from inactive compounds for both being docked into the same receptor.     

Lessons in molecular recognition. 2. Assessing and improving cross-docking accuracy

Docking methods are used to predict the manner in which a ligand binds to a protein receptor. Many studies have assessed the success rate of programs in self-docking tests, whereby a ligand is docked into the protein structure from which it was extracted. Cross-docking, or using a protein structure from a complex containing a different ligand, provides a more realistic assessment of a docking program's ability to reproduce X-ray results. In this work, cross-docking was performed with CDocker, Fred, and Rocs using multiple X-ray structures for eight proteins (two kinases, one nuclear hormone receptor, one serine protease, two metalloproteases, and two phosphodiesterases). While average cross-docking accuracy is not encouraging, it is shown that using the protein structure from the complex that contains the bound ligand most similar to the docked ligand increases docking accuracy for all methods ("similarity selection"). Identifying the most successful protein conformer ("best selection") and similarity selection substantially reduce the difference between self-docking and average cross-docking accuracy. We identify universal predictors of docking accuracy (i.e., showing consistent behavior across most protein-method combinations), and show that models for predicting docking accuracy built using these parameters can be used to select the most appropriate docking method.     

Structural models of protein-DNA complexes based on interface prediction and docking

Protein-DNA interactions are the physical basis of gene expression and DNA modification. Structural models that reveal these interactions are essential for their understanding. As only a limited number of structures for protein-DNA complexes have been determined by experimental methods, computation methods provide a potential way to fill the need. We have developed the DISPLAR method to predict DNA binding sites on proteins. Predicted binding sites have been used to assist the building of structural models by docking, either by guiding the docking or by selecting near-native candidates from the docked poses. Here we applied the DISPLAR method to predict the DNA binding sites for 20 DNA-binding proteins, which have had their DNA binding sites characterized by NMR chemical shift perturbation. For two of these proteins, the structures of their complexes with DNA have also been determined. With the help of the DISPLAR predictions, we built structural models for these two complexes. Evaluations of both the DNA binding sites for 20 proteins and the structural models of the two protein-DNA complexes against experimental results demonstrate the significant promise of our model-building approach.     

基于分子对接的苯丙素甙（PPGs）类化合物的虚拟筛选和合理设计

采用虚拟化合物生成法对抗肿瘤的苯丙素甙(PPGs)类化合物进行了配体受体对 接研究。以三种不同的骨架结构为基础分别生成了五十个虚拟苯丙素甙(PPGs)类化 合物，并将它们与端粒DNA受体进行分子对接，分析已知结构的对接结果，通过虚 拟筛选的方法得到了一批与受体相互作用能较高并且复合物能量较低的新的有潜力 的活性化合物。该方法可以弥补分子对接研究中，只能计算药物与受体的相互作用 ，无法有效设计新化合物的不足。这种方法在基于结构的药物分子设计中具有重要 的意义。     

Surrogate docking: structure-based virtual screening at high throughput speed

Summary Structure-based screening using fully flexible docking is still too slow for large molecular libraries. High quality docking of a million molecule library can take days even on a cluster with hundreds of CPUs. This performance issue prohibits the use of fully flexible docking in the design of large combinatorial libraries. We have developed a fast structure-based screening method, which utilizes docking of a limited number of compounds to build a 2D QSAR model used to rapidly score the rest of the database. We compare here a model based on radial basis functions and a Bayesian categorization model. The number of compounds that need to be actually docked depends on the number of docking hits found. In our case studies reasonable quality models are built after docking of the number of molecules containing 50 docking hits. The rest of the library is screened by the QSAR model. Optionally a fraction of the QSAR-prioritized library can be docked in order to find the true docking hits. The quality of the model only depends on the training set size – not on the size of the library to be screened. Therefore, for larger libraries the method yields higher gain in speed no change in performance. Prioritizing a large library with these models provides a significant enrichment with docking hits: it attains the values of 13 and 35 at the beginning of the score-sorted libraries in our two case studies: screening of the NCI collection and a combinatorial libraries on CDK2 kinase structure. With such enrichments, only a fraction of the database must actually be docked to find many of the true hits. The throughput of the method allows its use in screening of large compound collections and in the design of large combinatorial libraries. The strategy proposed has an important effect on efficiency but does not affect retrieval of actives, the latter being determined by the quality of the docking method itself. Electronic supplementary material is available at http://dx.doi.org/10.1007/s10822-005-9002-6.     

Naringenin and quercetin – potential anti-HCV agents for NS2 protease targets

Nonstructural proteins of hepatitis C virus had drawn much attention for the scientific fraternity in drug discovery due to its important role in the disease. 3D structure of the protein was predicted using molecular modelling protocol. Docking studies of 10 medicinal plant compounds and three drugs available in the market (control) with NS2 protease were employed by using rigid docking approach of AutoDock 4.2. Among the molecules tested for docking study, naringenin and quercetin revealed minimum binding energy of ? 7.97 and ? 7.95 kcal/mol with NS2 protease. All the ligands were docked deeply within the binding pocket region of the protein. The docking study results showed that these compounds are potential inhibitors of the target; and also all these docked compounds have good inhibition constant, vdW+Hbond+desolv energy with best RMSD value.     

Detailed analysis of grid-based molecular docking: A case study of CDOCKER-A CHARMm-based MD docking algorithm

The influence of various factors on the accuracy of protein-ligand docking is examined. The factors investigated include the role of a grid representation of protein-ligand interactions, the initial ligand conformation and orientation, the sampling rate of the energy hyper-surface, and the final minimization. A representative docking method is used to study these factors, namely, CDOCKER, a molecular dynamics (MD) simulated-annealing-based algorithm. A major emphasis in these studies is to compare the relative performance and accuracy of various grid-based approximations to explicit all-atom force field calculations. In these docking studies, the protein is kept rigid while the ligands are treated as fully flexible and a final minimization step is used to refine the docked poses. A docking success rate of 74% is observed when an explicit all-atom representation of the protein (full force field) is used, while a lower accuracy of 66-76% is observed for grid-based methods. All docking experiments considered a 41-member protein-ligand validation set. A significant improvement in accuracy (76 vs. 66%) for the grid-based docking is achieved if the explicit all-atom force field is used in a final minimization step to refine the docking poses. Statistical analysis shows that even lower-accuracy grid-based energy representations can be effectively used when followed with full force field minimization. The results of these grid-based protocols are statistically indistinguishable from the detailed atomic dockings and provide up to a sixfold reduction in computation time. For the test case examined here, improving the docking accuracy did not necessarily enhance the ability to estimate binding affinities using the docked structures.     

TreeDock: a tool for protein docking based on minimizing van der Waals energies

Predicting protein-protein and protein-ligand docking remains one of the challenging topics of structural biology. The main problems are (i) to reliably estimate the binding free energies of docked states, (ii) to enumerate possible docking orientations at a high resolution, and (iii) to consider mobility of the docking surfaces and structural rearrangements upon interaction. Here we present a novel algorithm, TreeDock, that addresses the enumeration problem in a rigid-body docking search. By representing molecules as multidimensional binary search trees and by exploring a sufficient number of docking orientations such that two chosen atoms, one from each molecule, are always in contact, TreeDock is able to explore all clash-free orientations at very fine resolution in a reasonable amount of time. Due to the speed of the program, many contact pairs can be examined to search partial or complete surface areas. The deterministic systematic search of TreeDock is in contrast to most other docking programs that use stochastic searches such as Monte Carlo or simulated annealing methods. At this point, we have used the Lennard-Jones potential as the only scoring function and show that this can predict the correct docked conformation for a number of protein-protein and protein-ligand complexes. The program is most powerful if some information is known about the location of binding faces from NMR chemical-shift perturbation studies, orientation information from residual dipolar coupling, or mutational screening. The approach has the potential to include docking-site mobility by performing molecular dynamics or other randomization methods of the docking site and docking families to families of structures. The performance of the algorithm is demonstrated by docking three complexes of immunoglobulin superfamily domains, CD2 to CD58, the V(alpha) domain of a T-cell receptor to its V(beta) domain, and a T-cell receptor to a pMHC complex as well as a small molecule inhibitor to a phosphatase.     

Docking study of cistanoside C to telomeric DNA fragment

Experiments show that the natural products phenyl propanoid glycosides (PPGs) extracted from the plant Pedicularis spicata are capable of repairing DNA damaged by oxygen radicals. Based on kinetic measurements and experiments on tumor cells, a theoretical study of the interaction between PPG molecule Cistanoside C and telomeric DNA fragment has been carried out. The docking calculations performed using JUMNA software showed that the Cistanoside C could be docked into the minor groove of telomeric DNA and form complexes with the geometry suitable for an electron transfer between guanine radical and the ligand. Such complexes can be formed without major distortions of DNA structure and are further stabilized by the interaction with the saccharide side-groups.