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1.
在现代药物的研发过程中,能够检测药物分子化学组成、结构及其与生物分子相互作用的新方法、新技术始终是人们最关注的科学问题之一。而光谱分析(包括红外、紫外和核磁共振)是最常用的分析手段。其中,核磁共振波谱技术通过检测组成有机化合物分子的原子核在周围化学环境影响下的跃迁规律,来获得反映核相关性质的参数,而这些参数包含了详尽的有机化合物分子结构和分子间相互作用的信息。核磁共振波谱能在液态、固态、气态,甚至在生物原位环境等多种复杂条件下,提供体系中分子组成、原子水平分辨率的三维结构、相互作用和动态过程等丰富信息,特别是药物研发中极其重要的药物分子与生物大分子的相互作用信息。因此核磁共振波谱在药物研发中发挥了越来越重要的作用,近年来在药物研发领域的应用是越来越广泛。而有关核磁共振波谱专门应用于药物研发方面的综述并不多见。由此,在简单阐述核磁共振波谱基本原理的基础上,从药物靶标生物大分子受体的结构与动力学、药物设计与筛选,以及药物代谢三方面综述了近年来核磁共振波谱在药物研发中的最新应用进展,以期系统的为分析工作者们提供核磁共振波谱在该领域目前的研究概貌。  相似文献   

2.
在现代药物的研发过程中, 能够检测药物分子化学组成、结构及其与生物分子相互作用的新方法、新技术始终是人们最关注的科学问题之一。而光谱分析(包括红外、紫外和核磁共振)是最常用的分析手段。其中, 核磁共振波谱技术通过检测组成有机化合物分子的原子核在周围化学环境影响下的跃迁规律, 来获得反映核相关性质的参数, 而这些参数包含了详尽的有机化合物分子结构和分子间相互作用的信息。核磁共振波谱能在液态、固态、气态, 甚至在生物原位环境等多种复杂条件下, 提供体系中分子组成、原子水平分辨率的三维结构、相互作用和动态过程等丰富信息, 特别是药物研发中极其重要的药物分子与生物大分子的相互作用信息。因此核磁共振波谱在药物研发中发挥了越来越重要的作用, 近年来在药物研发领域的应用是越来越广泛。而有关核磁共振波谱专门应用于药物研发方面的综述并不多见。由此, 在简单阐述核磁共振波谱基本原理的基础上, 从药物靶标生物大分子受体的结构与动力学、药物设计与筛选, 以及药物代谢三方面综述了近年来核磁共振波谱在药物研发中的最新应用进展, 以期系统的为分析工作者们提供核磁共振波谱在该领域目前的研究概貌。  相似文献   

3.
核物理与工农业发展   总被引:1,自引:0,他引:1  
郑涛 《物理》2012,41(5):309-315
核物理应用主要包括核分析技术、同位素技术和离子束技术的应用,这些应用在工农业生产中发挥着巨大作用.离子束、电子束和同位素辐射源被广泛应用于辐照探伤、辐照加工、辐照消毒、辐照育种、辐照杀虫、辐照保藏等方面.核物理应用新技术将成为人类生活中重要的组成部分,正确认识核辐射并掌握基本的辐射防护知识具有重要意义.文章介绍了核物理在工业和农业中的应用及其社会效益和经济效益.  相似文献   

4.
脂肪细胞脂肪酸结合蛋白A-FABP(Adipocyte fatty-acid binding protein)是治疗脂质调节生物过程相关疾病的重要靶标.采用分子动力学模拟和MM-PBSA方法研究抑制剂8CA与A-FABP结合模式,结果表明静电相互作用和范德华作用驱动了抑制剂8CA与A-FABP的结合.基于残基的能量分解表明抑制剂8CA与R126间的极性相互作用为抑制剂与A-FABP的结合提供了重要贡献,该残基与8CA的相互作用较好地稳定了抑制剂与A-FABP复合物的稳定性.期望该研究可为治疗炎症、动脉硬化和代谢病药物设计提供一定的理论指导.  相似文献   

5.
用NMR技术研究蛋白质-配体相互作用   总被引:1,自引:1,他引:0  
林东海  洪晶 《波谱学杂志》2005,22(3):321-341
蛋白质-配体相互作用的研究对理解生命过程、药物设计和药物筛选具有相当重要的科学意义和巨大的经济价值. NMR是研究蛋白质-配体相互作用的最有用的技术之一,有着显著的优势. 本文综述了近年来国际上用NMR技术研究蛋白质-配体相互作用的发展状况和趋势,先介绍表征蛋白质-配体相互作用的重要参数,然后介绍如何判断蛋白质或配体与复合物的化学交换类型以及所能获得的有关蛋白质-配体相互作用的信息,最后介绍具体用于研究蛋白质-配体相互作用的若干NMR技术以及基于NMR的药物筛选技术.  相似文献   

6.
包含SET结构域的核受体结合蛋白1(NSD1)是一种组蛋白甲基转移酶,它能够特异性的甲基化组蛋白H3赖氨酸第36位(H3K36).异常表达的NSD1主要发现于Sotos综合症患者体内,但它同样也能导致其他多种人类疾病的发生.目前已有靶向组蛋白甲基转移酶DOT1L和EZH2的小分子抑制剂报道,然而,靶向NSD1的化学探针分子尚未被发现.本文使用基于片段的核磁共振(NMR)筛选方法寻找到3个以NSD1蛋白作为靶点的苗头化合物,利用化学位移扰动分析技术测定了这些化合物与NSD1的结合亲和力.另外,利用分子对接方法选择获得苗头化合物与NSD1蛋白的最可能的结合模型.结果显示苗头化合物1结合于NSD1天然底物S-腺苷酸甲硫氨酸(SAM)的结合口袋中.我们的研究成果为进一步以结构为指导的从苗头化合物到先导化合物的衍化奠定了基础.  相似文献   

7.
摘要:脂肪细胞脂肪酸结合蛋白A-FABP(Adipocyte fatty-acid binding protein)是治疗脂质调节生物过程相关疾病的重要靶标. 分子动力学模拟和MM-PBSA方法被采用研究抑制剂8CA与A-FABP结合模式. 研究结果表明静电相互作用和范德华作用驱动了抑制剂8CA与A-FABP的结合。基于残基的能量分解表明抑制剂8CA与R126间的极性相互作用为抑制剂与A-FABP的结合提供了重要贡献. 该残基与8CA的相互作用较好地稳定了抑制剂与A-FABP复合物的稳定性. 我们期望这个研究能为治疗炎症、动脉硬化和代谢病药物设计提供一定的理论指导。  相似文献   

8.
采用Topomer CoMFA方法对21个苯磺酰基亚胺噻唑衍生物进行三维定量构效关系研究,得到了HIV-1非核苷类逆转录酶抑制剂的3D-QSAR模型,其拟合复相关系数r2=0.964,交互验证复相关系数q2=0.801,外部验证复相关系数Qext2=0.959;采用基于片段的药物设计方法 Topomer Search从ZINC数据库中虚拟筛选出3个Ra基团和7个Rb基团,且设计得到21个新化合物.结果表明:该模型不仅稳定性良好,而且具有较强的预测能力;采用Topomer Search技术能够有效的筛选进而设计出新的化合物,为抗艾滋病新药的设计提供理论依据.  相似文献   

9.
摘要:脂肪细胞脂肪酸结合蛋白A-FABP(Adipocyte fatty-acid binding protein)是治疗脂质调节生物过程相关疾病的重要靶标. 分子动力学模拟和MM-PBSA方法被采用研究抑制剂8CA与A-FABP结合模式. 研究结果表明静电相互作用和范德华作用驱动了抑制剂8CA与A-FABP的结合。基于残基的能量分解表明抑制剂8CA与R126间的极性相互作用为抑制剂与A-FABP的结合提供了重要贡献. 该残基与8CA的相互作用较好地稳定了抑制剂与A-FABP复合物的稳定性. 我们期望这个研究能为治疗炎症、动脉硬化和代谢病药物设计提供一定的理论指导。  相似文献   

10.
北京布鲁克仪器有限公司于1993年8月11~14日在北京举行了用户及NMR学术交流会议和“核磁共振在化学、生物及医学方面的无穷潜力”座谈会。同时在Bruker ARX一300谱仪上进行了新技术演示,并与北京大学ARX-400进行了联网。来自60多个单位的120多名核磁行家参加了会议。著名核磁专家,1991年诺贝尔化学奖获得者,瑞士联邦学院(ETH)R.R.Ernst教授到会并作了专题讲座;D.Moskau博士和J.Sonderegger先生介绍了当前核磁新技术及新硬件。会上有14位用户(包括一名台湾用户)分别从不同学科介绍了自己的工作。  相似文献   

11.
NMR based ligand screening is becoming increasingly important for the very early stages of drug discovery. We have proposed a method that makes highly efficient use of a single sample of a scarce target, or one with poor or limited solubility, to screen an entire compound library. This comparative method is based on immobilizing the target for the screening procedure. In order to support the method, a dual cell, flow injection probe with a single receiver coil has been constructed. The flow injection probe has been mated to a single high performance pump and sample handling system to enable the automated analysis of large numbers of compound mixes for binding to the target. The probe, having an 8 mm 1H/2H dual tuned coil and triple axis gradients, is easily shimmed and yields NMR spectra of comparable quality to a standard 5 mm high-resolution probe. The lineshape in the presence of a solid support is identical to that in glass NMR tubes in a 5 mm probe. Control spectra of each cell are identical and well separated, while ligand binding in a complex mixture can be readily detected in 20-30 min, thus paving the way for use of the probe for actual drug discovery efforts.  相似文献   

12.
核磁共振波谱在药物发现中的应用   总被引:2,自引:2,他引:2  
核磁共振波谱通过检测组成有机化合物分子的原子核跃迁而得到反映核性质的参数以及周围化学环境对这些参数的影响规律. 这些参数的相关内容包含了极其详尽的有机化合物分子结构和分子间相互作用的信息,并构成了核磁共振结构解析和生物靶分子-配体相互作用研究的理论基础. 在生物医药研发领域内,科研院所和公司企业的研发工作者们一直在努力探索利用核磁共振波谱监测生物靶分子-配体相互作用作为药物发现工具的潜能. 本文旨在针对核磁共振波谱在药物发现过程中活性化合物筛选的最新研究进展进行综述.  相似文献   

13.
High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.  相似文献   

14.
Summary The synthesis of structural analogs and the process of drug discovery have evolved dramatically through recent advances in solid-phase synthesis reagents and automated screening systems. As molecular diversity strategies emerge, the need for automated target-based selection of lead candidates becomes equally important. Multidimensional automated chromatographic techniques coupled to electrospray ionization mass spectrometry facilitate the selection process and provide maximum characterization information in a single screening run. The capture of tightly bound affinity leads by target biomolecules, followed by subsequent release and high-resolution separation with sensitive detection, significantly reduces the time required to identify and characterize lead compounds. This automated multidimensional chromatographic approach coupled with mass spectrometry, Selectronics, was used with several organic and natural libraries to demonstrate an automated target-based screening technique to select for high-affinity binders as potential lead compounds.Abbreviations ESI electrospray ionization - HPLC high-performance liquid chromatography - HTS high-throughput screening - ESI-TOF electrospray ionization time-of-flight - SAR structure-activity relationship  相似文献   

15.
Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of Compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anti-cancer drugs. These illustrate library focusing strategies.  相似文献   

16.
Synthesis and screening of combinatorial librariesfor pharmaceutical lead discovery is a rapidlyexpanding field. Oligo-N-substituted glycines (NSGs)were one of the earliest sources of moleculardiversity in combinatorial libraries. In one of thefirst demonstrations of the power of combinatorialchemistry, two NSG trimers, CHIR-2279 and CHIR-4531,were identified as nM ligands for two 7-transmembraneG-protein-coupled receptors. The NMR characterizationof these two lead compounds was undertaken to verifycovalent connectivity and to determine solutionconformations, if any. The sequential chemical shiftassignments were performed using a new strategy forassigning 1H and 13C resonances of NSGs. The conformational preferences were then determined inboth an aqueous co-solvent system and an organicsolvent to probe the effects of hydrophobic collapse. NSGs are expected to be more flexible than peptidesdue to the tertiary amide, with both cis andtrans amide bond conformations being accessible. Solution NMR studies indicate that although CHIR-2279and CHIR-4531 have identical backbones and termini,and very similar side chains, they do not display thesame solution conformational characteristics.  相似文献   

17.
The discovery of new or improved catalysts is often an arduous task. In several instances, empirical studies and single reactor experiments have given way to design of experiments methods and high throughput experimentation (HTE) to speed up the process. However, even with increased throughput, only small subsets of the large multivariate parameter spaces often associated with catalyst and process characteristics can be sampled. An approach termed rational design gives the opportunity to target regions of the parameter space by combining the knowledge gained from surface science experiments and modeling to efficiently guide HTE. The prediction and validation of bimetallic catalysts for ethylene epoxidation illustrates this approach. Conversely, HTE can also be used to lead the discovery cycle in reverse, identifying surface science and modeling opportunities for further development. As an example of this cycle, the use of HTE to identify model catalyst designs for the study of promoted NSR catalysts is considered.  相似文献   

18.
倪晋平  田会  杨雷 《光学技术》2008,34(1):152-155
针对战斗部常规生产检验,提出了采用多个光幕靶、数据采集仪和位置标识器进行测速的方法。光幕靶探测破片穿过的时刻,数据采集仪记录波形并提取破片穿过光幕靶的时间,位置标识器可以识别破片飞行的方向角度,从而计算破片实际飞行的靶距。介绍了测速系统的组成,光幕靶设计以及测速系统的冲击与破片杀伤防护措施。采用战斗部静爆试验验证了所提方法,结果表明所提方法准确有效。给出了破片穿过光幕的瞬态波形。  相似文献   

19.
采用核磁共振(NMR)技术对吡虫啉生产过程中吗啉精馏后的副产物进行了定性定量分析.二维扩散排序谱(2D DOSY)表明该产物由两种化合物组成.对样品的核磁共振氢谱(1H NMR)、二维扩散排序谱(2D DOSY)、碳谱(13C NMR)、DEPT、氢-氢相关谱(1H-1H COSY)、碳氢相关谱(HSQC)与碳氢远程相关谱(HMBC)进行了解析,对其所有的NMR谱信号进行了归属,确定样品所含的两种主要组份为双吗啉和烯胺.最后采用定量13C NMR技术得到了该精馏副产物中双吗啉和烯胺组成的摩尔比例为1∶4.  相似文献   

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