Calculation of relative binding affinities of fructose 1,6-bisphosphatase mutants with adenosine monophosphate using free energy perturbation method

The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this article, the importance of hydrophobic and hydrophilic residues to the binding of adenosine monophosphate (AMP) to the fructose 1,6-bisphosphatase (FBPase), a target enzyme for type-II diabetes, was examined by FEP method. Five mutations were made to the FBPase enzyme with AMP inhibitor bound: 113Tyr --> 113Phe, 31Thr --> 31Ala, 31Thr --> 31Ser, 177Met --> 177Ala, and 30Leu --> 30Phe. These mutations test the strength of hydrogen bonds and van der Waals interactions between the ligand and enzyme. The calculated relative free energies indicated that: 113Tyr and 31Thr play an important role, each via two hydrogen bonds affecting the binding affinity of inhibitor AMP to FBPase, and any changes in these hydrogen bonds due to mutations on the protein will have significant effect on the binding affinity of AMP to FBPase, consistent to experimental results. Also, the free energy calculations clearly show that the hydrophilic interactions are more important than the hydrophobic interactions of the binding pocket of FBPase.     

表面张力实验装置的改进

本针对拉脱法测量液体表面张力实验中仪器误差较大,测量结果不理想的情况,对该实验装置进行了改进,使测量数据离散性小、精度高。     

清除试剂在液相组合化学中的应用

综述了近年来清除试剂在液相组合化学中的应用,并介绍了一些采用清除试剂对液相化合物库进行分离和纯化的实例。对清除试剂进行了分类,各类清除试剂参与的液相反应以及被清除的非目标产物类型也作了相应的介绍。     

基于MCPT解法器库的专用辐射探测模拟软件研发与应用北大核心CSCD

甲状腺内^(131)I放射性活度与辐射探测结果的比例关系与甲状腺几何尺寸、探测距离等因素相关,是估算甲状腺内^(131)I含量与其可能造成的辐照损伤的关键参数。基于MCPT辐射输运数值模拟算法器库开发了用于开展NaI探测器伽马辐射测量模拟的应用程序,进而建立了多组具有不同容积的甲状腺型容器和不同探测距离的物理模型,最终通过蒙特卡罗数值计算得到了不同测量状态下探测器的探测效率。在甲状腺型容器与探测器距离较远时,数值模拟给出的结果与理论计算结果一致,证明此应用程序可用于定量分析NaI的探测效率。数值模拟结果表明,小距离模型的结果受甲状腺样容器的大小和距离的显著影响,模拟给出的探测效率表为开展深入细致的实验研究奠定了基础。     

螺旋线螺纹模型的有限元分析

针对精细化模型与Abaqus摩擦模型所存在问题, 提出一种基于螺纹几何特征的螺旋线螺纹模型, 采用脚本语言实现了螺旋线螺纹模型生成自动化, 并应用到某发动机机体主轴承盖螺栓螺孔的强度分析. 分析结果表明, 仿真计算得到的螺栓及机体螺孔处的应力很好地表征了螺栓连接结构螺纹处的实际应力分布, 与螺纹精细模型相近, 比Abaqus摩擦模型精度更高, 且计算方便、实用、高效, 验证了本文方法的准确、可行.     

The multiple roles of computational chemistry in fragment-based drug design

Fragment-based drug discovery (FBDD) represents a change in strategy from the screening of molecules with higher molecular weights and physical properties more akin to fully drug-like compounds, to the screening of smaller, less complex molecules. This is because it has been recognised that fragment hit molecules can be efficiently grown and optimised into leads, particularly after the binding mode to the target protein has been first determined by 3D structural elucidation, e.g. by NMR or X-ray crystallography. Several studies have shown that medicinal chemistry optimisation of an already drug-like hit or lead compound can result in a final compound with too high molecular weight and lipophilicity. The evolution of a lower molecular weight fragment hit therefore represents an attractive alternative approach to optimisation as it allows better control of compound properties. Computational chemistry can play an important role both prior to a fragment screen, in producing a target focussed fragment library, and post-screening in the evolution of a drug-like molecule from a fragment hit, both with and without the available fragment-target co-complex structure. We will review many of the current developments in the area and illustrate with some recent examples from successful FBDD discovery projects that we have conducted.     

图书馆知识管理的多层次模糊综合评价方法

根据系统评价原则,采用调查问卷与数学定量研究相结合的处理方法,用模糊综合评价法来评价图书馆知识管理绩效.通过图书馆知识管理绩效评价的实证分析,证明评价指标的科学性、合理性以及切实可行性.     

Establishment of a knowledge base for identification of residual solvents in pharmaceuticals

A knowledge base for identification of residual solvents in pharmaceuticals has been established using gas chromatograph-mass spectrometry (GC-MS) and gas chromatograph-Fourier transform infrared spectrometry (GC-FTIR). Sixty solvents were studied according to the guideline for residual solvents regulated by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The standard mass spectra library, the limit of detection (LOD) mass spectra library, the standard vapor-phase infrared spectra library, and the limit of detection (LOD) vapor-phase infrared spectra library were established and constituted the knowledge base. Using the knowledge base, the problem of qualitation, which was the difficulty of determining residual solvents, can be resolved.