Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism

The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2 (ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined K_m values ranged from 0.05 to 0.3 μM and k_cat values from 2.3 to 17.6 min⁻¹, while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup. This mutation increased the retinoid activity up to 100-fold. The K_m values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic retinol oxidation at physiological concentrations. Received 12 October 2006; received after revision 6 December 2006; accepted 8 January 2007     

基于网络药理学和分子对接探讨智脑胶囊改善阿尔茨海默病的作用机制

借助网络药理学和分子对接技术,探讨智脑胶囊改善阿尔茨海默病的干预机制。通过TCMSP、TCMID等多个数据库寻找与智脑胶囊相关的化学成分及其作用靶点;利用GeneCard等数据库获取阿尔茨海默病的作用靶点;运用Venny2.1网站筛选出药物与疾病的交集靶点;使用STRING平台和Cytoscape软件进行拓扑分析得到智脑胶囊治疗阿尔茨海默病的核心作用靶点;采用Metaspace数据库对潜在核心作用靶点进行GO(gene ontology)及KEGG(Kyoto encyclopedia of genes and genomes)通路富集分析;利用AutoDock软件使用分子对接验证活性化合物与核心靶点的结合能力。结果表明：在智脑胶囊中共筛选出44个活性成分和292个有效靶点,智脑胶囊与阿尔茨海默病共同靶点58个;蛋白质-蛋白质相互作用得出关键靶点包括AKT1、IL-6、TNF等;GO分析共包含1 419条,KEGG得到175条代谢通路,主要包括脂质与动脉硬化、TNF信号通路;分子对接显示关键成分与靶点具有良好的结合能力。研究表示智脑胶囊可能通过脂质与动脉硬化和TNF信号通路等途径来减轻...     

药物分子对接网格研究与进展

药物分子对接所涉及的搜索空间非常巨大，需要耗费大量的时间，并且对计算环境也有较高的要求．将网格技术应用于药物分子对接中，能有效解决上述问题．通过应用改进的遗传算法多种群竞争机制的对接演化模型GADock，以信息熵控制设计空间的收缩，增强了进化的有效性，显著地提高了对接效率、利用网格数据传输和网格任务调度等网格技术对分子对接过程进行了优化，有效利用了网格节点资源，并降低了药物分子的对接时间．实例测试表明了药物分子对接与网格技术相结合的合理性及有效性．     

基于TCMSP抗肿瘤中药小分子EGFR-TKI的研究

目的研究分析中药小分子表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)的抗肿瘤情况。方法挖掘中药系统药理学数据库与分析平台(TCMSP)中药小分子表皮生长因子受体抑制剂,利用反向分子对接服务器(DRAR-CPI)进行靶点验证。结果木犀草素、槲皮素、金雀异黄酮、表没食子儿茶素没食子酸酯、漆黄素5种中药小分子与表皮生长因子受体(EGFR)结合良好。结论中药小分子EGFR-TKI能从多个靶点、多种途径抑制肿瘤细胞的生长和扩散,利用中药小分子开发新一代多靶点EGFR-TKI具有广阔的前景。     

中国载人交会对接技术的设计与实现

中国在载人航天工程第二步第一阶段任务中,自主研制了天宫一号目标飞行器和神舟八号、神舟九号、神舟十号载人飞船,通过3次在轨飞行任务完成了8次交会、6次对接,覆盖了自动和手动等多种交会对接模式,突破并掌握了交会对接技术.从交会对接系统、交会轨道、交会测量和控制、信息传输、对接与分离、飞行方案,以及试验验证等方面对中国载人交会对接设计的技术特点、所采用的创新技术方法和解决的技术难题进行了介绍,在飞行验证的基础上分析了工程任务取得的成果,与国际水平进行了综合比较,对中国载人交会对接技术的设计和研制情况进行了总结.     

飞船空间对接机构技术

空间对接是载人航天工程的关键技术,本文讨论了我国神舟对接机构的系统方案,分析了对接捕获和缓冲的动力学设计、机构学设计,以及对接机构连接刚度的保证等方面问题,讨论了对接机构地面试验系统和试验方案,介绍了我国首次空间对接的情况.     

以总加权完工时间为目标的两台机越库排序的动态规划算法

提出并研究两台机器环境下的以带权总完工时间为目标函数的越库配送排序问题.越库作业的入库与出库车辆被看作是排序问题中的机器,入库货物与客户需求为具有前序集限制关系的被加工工件.研究了该问题的计算复杂性及其最优解的若干性质,提出求解该问题的逆向动态规划算法,并给出了动态规划算法的数值实验.结果表明,所提出算法至少可以求解25个工件规模的越库配送排序问题.     

考虑不确定性的船舶坐墩配墩优化

提出了一个考虑支墩组合刚度不确定性的船舶坐墩支墩配置优化设计的数学模型。用凸处理支墩组合刚度的不确定性，用分级优化方法求解所提出的优化模型。并讨论了支墩组合刚度不确定性程度对设计结果的影响。计算结果表明，考虑参数不确定性后，配墩方案发生了变化，支墩结构质量也有所增加。增加的支墩材料是用于提高结构物抵抗不确定性参波动变化的能力。     

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Aldose reductase is involved in the polyol pathway, catalyzing the reduction of glucose to sorbitol. However, due to pronounced binding site adaptations, the enzyme can operate on a broad palette of structurally diverse substrates ranging from small aliphatic and aromatic aldehydes up to steroid-type ligands. A comparative analysis of the presently accessible crystal structures of aldose reductase complexes reveals four binding-competent protein conformations. Additional relevant conformers are detected through molecular dynamics simulations. They indicate an equilibrium of several conformers which is shifted towards the binding-competent geometries upon ligand binding. Such a manifold system with several alternative binding site conformers requires some tailored concepts in virtual screening. We followed two strategies, both successfully suggesting new micromolar inhibitors. In a first attempt, we concentrated on one preferred conformer and performed a virtual screening, assuming that the binding pocket of aldose reductase adopts only this conformation. In a second approach, we followed a ligand superpositioning method. Ligands were extracted in their bound conformations from three different crystal structures, all accommodating the ligands with different active site conformations. After merging these ligands into one supermolecule, mutual alignments were computed, taking candidate ligands from a screening database. The latter strategy also retrieved several structurally new inhibitors of micromolar potency.