DNA依赖蛋白激酶抑制剂的CoMFA研究

运用比较分子力场分析方法(CoMFA),以DNA依赖蛋白激酶(DNA-PK)抑制剂分子为研究对象,建立1组对DNA依赖蛋白激酶有抑制活性化合物的三维定量构效关系(3D-QSAR)模型,探索其活性数据和三维结构参数的关系,所建最佳模型交叉验证相关系数q2=0.670,非交叉验证相关系数R2=0.993,标准偏差SD=0.053,说明该模型预测能力较好.根据CoMFA模型的三维等势图可知,小体积、电负性大的取代基团,能提高该类化合物的活性,为新型DNA-PK抑制剂分子的设计提供了理论依据.     

蛋白激酶活性及抑制性检测研究进展

蛋白激酶催化蛋白磷酸化是一种非常重要的蛋白质翻译后修饰方式,能够调节细胞内大多数蛋白的功能,在众多生理过程中发挥着至关重要的作用。磷酸化过程的异常以及激酶的过度表达往往与许多疾病密切相关,如癌症、糖尿病和老年痴呆症。因而,测定蛋白激酶的活性及筛选蛋白激酶抑制剂对基础生物医学研究和酶靶药物的开发是非常重要的。近年来,研究工作者们采用电化学法、比色法以及荧光检测法等方法研究了对蛋白激酶活性及抑制性的检测。该文回顾了蛋白激酶活性测定及抑制性检测的研究进展,主要关注了荧光检测法的应用,并对其未来的发展进行展望。     

基于Aurora协议的高速通信技术的研究

介绍了基于模块化方法在FPGA上实现高速通信的设计方案。系统在Aurora协议下采用高速串行收发器Rocket I/O,解决了不同端口收发时钟补偿带来的数据丢失问题,并结合SFP光模块对高速AD采样信号进行有效的传输。实验证明了方案的可行性,其对提高雷达信号处理带宽、改进雷达的探测性能具有较大的意义。     

基于Aurora协议的高速图像传输和通信平台设计

在红外、雷达跟踪等领域中,一个跟踪成像系统往往需要多块信号处理板进行协同工作,因此电路板与电路板之间需要进行高速图像传输和通信。在基于AURORA IP核的基础上构建了一个图像高速传输和通信平台,使得两块处理板之间的图像传输和通信可以通过一根光纤实现,不仅提高了图像传输和通信的速率,还大大简化了外围线路的复杂性。通过实验验证,所设计的图像高速传输和通信平台工作性能稳定,目前已应用于红外成像跟踪系统和雷达跟踪成像系统。     

基于PCI-Express和Aurora协议高速光纤通信板卡的实现

介绍了一种基于单片FPGA的高速光纤通信通信板卡,利用Aurora协议支持光纤传输,采用DMA控制逻辑通过PCI—Express接口与主机交换数据,着重阐述了板卡各个功能逻辑实现。实际的测试数据表明该系统具有高带宽、可扩展的特点。     

HIV蛋白酶抑制剂吡喃酮类化合物的QSAR研究

用MNDO量化方法计算了16个吡喃酮类化合物的电子结构参数和疏水参数，探讨了药物物理化学参数与电子结构参数对抑制IV蛋白酶的影响，得到一个线形关系显著的方程。结果表明，药物的疏水参数和分子中3个氧原子的净电荷之和是影响药物活性的主要因素。所得结果符合实验事实。     

一类伊马替尼衍生物酪氨酸激酶抑制剂作用模式的理论研究

第1代Bcr-Abl抑制剂伊马替尼问世以来取得了巨大的商业成功。本文对酪氨酸激酶和伊马替尼、尼罗替尼复合物晶体的结构(PDB ID:2HYY、3CS9)中伊马替尼、尼罗替尼的活性结构、药效团进行了分析研究,探讨了酪氨酸激酶与抑制剂的相互作用模式。研究表明伊马替尼分子结构中哌嗪基部分与酶作用较弱,没有明显的药效团,适合在此部分结构进行结构改造。基于69个伊马替尼衍生物抑制剂的结构和活性数据,利用遗传算法,建立了合理伊马替尼衍生物的定量构效关系。确定的酪氨酸激酶与抑制剂的作用模式,可以指导抑制剂的设计,用于开发新型抗癌药物。     

乙酰胆碱酯酶抑制剂虚拟筛选方法研究

在虚拟筛选过程中，虚拟筛选策略和方法是获取结果的基础，但需要通过实验数据来检验。获得虚拟筛选合理的限制因素，将为大规模虚拟筛选提供方法依据。通过建立乙酰胆碱酯酶抑制剂的活性检测方法，检测了4000多个化合物的生物活性，并发现了34个活性较高的化合物，同时将设计的6个不同的虚拟筛选方法分别用于2个乙酰胆碱醋酶抑制剂虚拟筛选模型。将所预测的可能活性化合物及两模型共有的可能活性化合物分别与实验所得的活性化合物对照，综合分析讨论虚拟筛选乙酰胆碱酯酶抑制剂的重要因素和进一步富集活性化合物的方法，为大规模的虚拟筛选乙酰胆碱醋酶抑制剂提供可靠依据，并为其他基于蛋白酶结构的虚拟筛选提供参考。     

酪氨酸激酶抑制剂的虚拟受体模型方法研究

利用柔性原子受体模型(FLARM)方法对一系列的异黄酮和喹诺酮衍生物表皮生长因子受体酪氨酸激酶抑制剂进行了三维定量构效关系研究,得到了合理的构效关系模型。FLARM方法的计算结果还给出了虚拟的受体模型,该模型说明了抑制剂与受体之间可能的相互作用。这些相互作用包括两个氢键和一个硫-芳香相互作用,以上结果仅仅是由7个化合物得到的。     

Molecular docking/dynamics studies of Aurora A kinase inhibitors

The binding modes of a known 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, quinazoline, pyrimidine and indolinone series of Aurora A kinase inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. Crystallographic bound compound 8 was precisely predicted by our docking procedure as evident from 0.43 Å root mean square (rms) deviations. In addition compound 25 (AZ_68) has been successfully cross-docked within the Aurora A kinase active site, which was pre-organized for inhibitor 8. We found four key sites (A: solvent-exposed front pocket, B: hinge region, C: selectivity pocket and D: solvent-exposed phosphate binding region) of the Aurora A kinase contributing towards the binding of these compounds. We suggest that the small hydrophobic substituents at C-6 position of pyrrolopyrazole nucleus (in compounds 1–8); C-6 and C-7 positions of the quinazoline moiety (in compounds 9–23); C-2 position of the quinazoline and C-4 position of the pyrimidine (in compound 25) could be more effective and selective through increased hydrophobic contacts and selectivity pocket interactions with these modifications of Aurora A kinase inhibitors. Five representative complexes were subjected to 1000 ps of MD simulation to determine the stability of the predicted binding conformations. The low value of the root mean square deviations (ranging from 0.725 to 1.820 Å) between the starting complex structure and the energy minimized final average complex structure suggests that the Glide Extra Precision (XP) derived docked complexes are in a state of near equilibrium. The structure-based drug design strategy described in this study will be highly useful for the development of new inhibitors with high potency and selectivity.     

Identification of p90 Ribosomal S6 Kinase 2 as a Novel Host Protein in HBx Augmenting HBV Replication by iTRAQ‐Based Quantitative Comparative Proteomics

Purpose

The aim of this study was to screen for novel host proteins that play a role in HBx augmenting Hepatitis B virus (HBV) replication.

Experimental design

Three HepG2 cell lines stably harboring different functional domains of HBx (HBx, HBx‐Cm6, and HBx‐Cm16) were cultured. ITRAQ technology integrated with LC‐MS/MS analysis was applied to identify the proteome differences among these three cell lines.

Results

In brief, a total of 70 different proteins were identified among HepG2‐HBx, HepG2‐HBx‐Cm6, and HepG2‐HBx‐Cm16 by double repetition. Several differentially expressed proteins, including p90 ribosomal S6 kinase 2 (RSK2), were further validated. RSK2 was expressed at higher levels in HepG2‐HBx and HepG2‐HBx‐Cm6 compared with HepG2‐HBx‐Cm16. Furthermore, levels of HBV replication intermediates were decreased after silencing RSK2 in HepG2.2.15. An HBx‐minus HBV mutant genome led to decreased levels of HBV replication intermediates and these decreases were restored to levels similar to wild‐type HBV by transient ectopic expression of HBx. After silencing RSK2 expression, the levels of HBV replication intermediates synthesized from the HBx‐minus HBV mutant genome were not restored to levels that were observed with wild‐type HBV by transient HBx expression.

Conclusion and clinical Relevance

Based on iTRAQ quantitative comparative proteomics, RSK2 was identified as a novel host protein that plays a role in HBx augmenting HBV replication.

     

Optimizing Kinase Assays for Ultrahigh-Throughput Profiling Using the Kinase-Glo Plus Assay

Kinase profiling is an important component of the drug discovery process. Profiling with IC50 provides simultaneous potency and selectivity information about compounds of interest. Profiling data assist in the detection of inhibitors that may have potential toxic effects due to off-target activity. Compounds that exhibit the strongest potency and specificity profiles can be identified as leads for further optimization. Miniaturizing this profiling process in uHTS format generates data from a wide range of compound concentrations, providing more meaningful and accurate information. The combination of the Kinase-Glo Plus Assay with low-volume liquid-dispensing equipment provides an excellent solution for assay optimization and kinase profiling.     

硝化抑制剂在农业上应用的研究进展

本文综述了硝化抑制剂在农业上应用的研究进展 ,包括硝化抑制剂的种类和作用机理、硝化抑制剂对农作物生长和产量的影响以及对环境保护的作用等 ,并指出了一些需要注意的问题     

光系统II抑制剂三维定量构效关系模型

光系统Ⅱ （ Ｐ ＳⅡ） 抑制剂通过抑制光合作用系统Ⅱ的电子传递使杂草因光合作用中断而死亡。本文选择不同骨架结构的 Ｐ ＳⅡ抑制剂, 由限定性构象搜索方法确定了重叠规则, 采用比较分子场分析方法进行了三维定量构效关系研究, 得出了具有较强预测能力的构效关系模型。     

硝化抑制剂对降低蔬菜硝酸盐积累的影响及其影响因素的研究进展

硝化抑制剂不仅能够提高蔬菜氮肥利用率和减少氮肥对环境的污染,有的能改善蔬菜品质。本文对硝化抑制剂对蔬菜硝酸盐累积的控制效果、作用机理、影响因素及其作用效果预测等作一综述,并对硝化抑制剂在蔬菜生产上研究与应用作了展望。     

Biomolecular Agents as Multi-behavioural Concurrent Objects

In recent years, there has been increasing interest in computational models of biological systems based on various calculi of communicating processes, such as the stochastic pi-calculus. These models make it possible to simulate and eventually visualize the dynamic evolution of complex biosystems in time and under varying environmental conditions.While the elegance of the pi-calculus lies in its minimality, this is also a drawback when it comes to modeling because much effort must be devoted to encoding high-level ideas into the low-level means that the language affords us.In this paper, we describe an on-going effort to design a new higher-level programming language that provides direct ontological support for the concepts which are used to formulate, organize and structure models of biomolecular systems.Our language has an object-oriented flavour where we view molecular components as agents with finite sets of behaviours (states). Reactions are modeled as exchanges over connected ports that may cause agents to switch states.     

基于级联分类器的乳腺癌病理学图像中有丝分裂检测*

有丝分裂检测与计数是诊断乳腺癌的一个重要指标,针对乳腺癌病理图像中的有丝分裂核与非有丝分裂核难区分、难检测等研究难点,本文提出了一个基于“级联分类器”的计算机辅助有丝分裂检测算法。1、考虑到分割后正负样本在数量上的差异性较大,该方法通过一个级联分类器在其每一层中丢弃一部分非有丝分裂块,使得级联中后一个分类器在训练时能更关注那些比较难分的样本。2、利用颜色直方图找出有丝分裂块与非有丝分裂块差异性较大的颜色通道,以便提取的特征具有更好的分类性能。该方法最终以Fmeasure值为0.732验证了所提算法的有效性。