A general protocol for creating high-throughput screening assays for reaction yield and enantiomeric excess applied to hydrobenzoin

A general approach to high-throughput screening of enantiomeric excess (ee) and concentration was developed by using indicator displacement assays (IDAs), and the protocol was then applied to the vicinal diol hydrobenzoin. The method involves the sequential utilization of what we define herein as screening, training, and analysis plates. Several enantioselective boronic acid-based receptors were screened by using 96-well plates, both for their ability to discriminate the enantiomers of hydrobenzoin and to find their optimal pairing with indicators resulting in the largest optical responses. The best receptor/indicator combination was then used to train an artificial neural network to determine concentration and ee. To prove the practicality of the developed protocol, analysis plates were created containing true unknown samples of hydrobenzoin generated by established Sharpless asymmetric dihydroxylation reactions, and the best ligand was correctly identified.     

From genetics and genomics to drug discovery: yeast rises to the challenge

Yeast expands its role from eukaryotic genetics and genomics to drug discovery.     

Targeting protein–protein interactions for cancer therapy

An increasing number of protein–protein interactions have been identified as potential intervention points for the development of anticancer agents. However, such systems have historically been considered high-risk targets due to the relatively large interaction surfaces involved in protein–protein binding. This characterization has to be reexamined as progress has been made recently in identifying small-molecule inhibitors of several protein–protein systems in oncology including the p53–MDM2 interaction. This review presents a survey of protein–protein interactions that have been identified as potential oncology targets and evaluates their attractiveness in terms of drug discovery. The analysis focuses primarily on the structural characteristics of the participating binding sites, particularly the dimensions of the sites. Known ligands are also examined, especially with regard to their druglikeness.     

Selectively primed adaptive driver RDA (SPAD-RDA): an improved method for subtractive hybridization

A modification of the Representational Difference Analysis (RDA) method for subtractive hybridization, termed Selectively Primed Adaptive Driver (SPAD) RDA, is described. It differs from conventional RDA primarily in the manner by which initial driver (D) and tester (T) amplicon complexities are determined, and by optimizing the composition of D with respect to T for each round of subtraction. Total nucleic acid is extracted from serum or plasma and converted to double-stranded DNA/cDNA. A polymerase chain reaction (PCR) primer containing a selective nucleotide(s) at its 3'-end is used to generate amplicons of reduced complexity. Parallel subtractions are carried out, D vs. T (DT) for enrichment of tester-unique sequences and D vs. D (Driver Control or DC) to generate an optimized driver for use in the subsequent round. Following each round, agarose gel electrophoresis is used to visually identify any DT-unique bands through a side-by-side comparison of DT and DC subtraction products. In comparison to conventional RDA, SPAD-RDA achieved greater enrichment of viral sequences from an HCV infected chimpanzee, resulting in isolation of 13.7% of the viral genome, and an overall enrichment for HCV sequences of 239-fold. Virus fragments were also obtained from an HCV-infected human sample subtracted against non-paired human driver sequences. J. Med. Virol. 71:150-159, 2003.     

化合物药物活性的高通量筛选

介绍高通量药物筛选系统的组成及其相关技术。结合国家药物筛选中心的工作,详细介绍了化合物药物活性的高通量筛选的４ 个组成部分及其在药物发现过程中的作用。高通量药物筛选系统是一个涉及多个学科的、以分子生物学、新型检测技术技术为基础的新型药物发现系统。高通量药物筛选系统的顺利开展可以加速我国的新药研究     

Capecitabine: Preclinical Pharmacology Studies

Capecitabine (N⁴-pentyloxycarbonyl-5-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate, which was designed to besequentially converted to 5-fluorouracil (5-FU) by three enzymes located inthe liver and in tumors; the final step is the conversion of5-deoxy-5-fluorouridine (5-DFUR) to 5-FU by thymidine phosphorylase (dThdPase) in tumors. In human cancer xenograft models, capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma ornormal tissue (muscle). The tumor 5-FU levels were also much higherthan those achieved by intravenous administration of 5-FU at equitoxic doses.Capecitabine and its intermediates are not cytotoxic by themselves,but become effective after their conversion to 5-FU. This tumor selectivedelivery of 5-FU ensured greater efficacy and a more favorable safety profilethan with other fluoropyrimidines. In 24 human cancer xenograft modelsstudied, capecitabine was more effective at a wider dose range andhad a broader spectrum of antitumor activity than 5-FU, UFT or itsintermediate metabolite 5-DFUR. The susceptibility of the xenografts tocapecitabine correlated with tumor dThdPase levels. Moreover, theconversion of 5-DFUR to 5-FU by dThdPase in tumor was insufficient in axenograft model refractory to capecitabine. In addition, the efficacy ofcapecitabine was enhanced by dThdPase up-regulators, such astaxanes and cyclophosphamide. The efficacy of capecitabine may, therefore, beoptimized by selecting the most appropriate patient population based on dThdPasestatus and/or by combining it with dThdPase up-regulators. Capecitabinehas additional characteristics not found with 5-FU, such as potentantimetastatic and anticachectic actions in mouse tumor models.With this profile, capecitabine may have substantial potential in cancer treatment.     

学科背景知识在医学文本特征抽取中的应用

分析目前科技文献文本特征抽取方法研究现状,将基于背景知识的TF-IDF方法应用到医学文本特征抽取中,在4个医学领域中进行试验对比,结果表明该方法在抽取词汇数量较少时可以显著提高抽取效果,在对文本集合中通用词的过滤及重要特征词的识别方面明显优于使用通用IDF的TF-IDF方法。