Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification

One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated K_i ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification.     

使用pFind软件深度检测蛋白质修饰

Tandem mass spectrometry-based protein identification provides a powerful means for large-scale mapping of post-translational modifications. However, due to the complexity of tandem mass spectra and the large number of modifications, comprehensive and efficient detection of modifications remains an unsolved problem. This paper briefly describes a new solution used by the pFind software for in-depth detection of modifications.     

PSICO: Solving Protein Structures with Constraint Programming and Optimization

In this paper we propose PSICO (Processing Structural Information with Constraint programming and Optimisation) as a constraint-based approach to determining protein structures compatible with distance constraints obtained from Nuclear Magnetic Resonance (NMR) data. We compare the performance of our proposed algorithm with DYANA (Dynamics algorithm for NMR applications) an existing commercial application based on simulated annealing. On a test case with experimental data on the dimeric protein Desulforedoxin, the method proposed here supplied similar results in less than 10 minutes compared to approximately 10 hours of computation time for DYANA. Although the quality of results can still be improved, this shows that CP technology can greatly reduce computation time, a major advantage because structural NMR technique generally demands multiple runs of structural computation.     

基于支持向量机的微阵列基因表达数据分析方法

DNA微阵列技术，使人们可以同时观测成千上万个基因的表达水平，对其数据的分析已成为生物信息学研究的焦点．针对微阵列基因表达数据维数高、样本小、非线性的特点，设计了一种基于支持向量机的基因表达数据分类识别方法，该方法采用信噪比进行基因特征提取，运用支持向量机的不同核函数进行性能测试，针对几个典型数据集的实验表明其识别效果良好．     

HGA-COFFEE:多序列比对问题的混合遗传算法求解

针对生物序列分析中的多序列比对问题，设计了一个求解多序列比对问题的混合遗传算法（与之相应的软件称为HGA-COFFEE），该算法采用COFFEE函数作为个体的适应度函数，构造了5种新的遗传算子，包括1种选择算子，2种交叉算子和2种变异算子，其中一种变异算子基于COFFEE的一致性信息设计，以改善算法的整体搜索能力；另一种变异算子基于动态规划方法设计，以增强其局部搜索能力。最后，通过对BAliBASE中144个测试例的测试，证明该算法是有效的，与已有的算法相比，该算法对处于朦胧区和具有N／C末端延伸的序列比对问题有更强的问题求解能力。     

INTRODUCTION TO THE SPECIAL ISSUE ON CASE-BASED REASONING IN THE HEALTH SCIENCES

There has been an explosion of interest in health sciences applications of case-based reasoning (CBR), not only in the traditional CBR in medicine domain, but also in bioinformatics, enabling home health-care technologies, CBR integration, and synergies between CBR and knowledge discovery. This special issue features the best papers from the third workshop on CBR in the health sciences, held at ICCBR-05 in Madrid. It is the third in a series of exciting workshops, the first two of which were held at ICCBR-03, in Trondheim, Norway, and at ECCBR-04, in Madrid, Spain. The nine high-quality papers introduced here represent the research and experience of twenty-two authors working in eight different countries on a wide range of problems and projects. These papers illustrate some of the major trends of current research in CBR in the health sciences, and represent overall an excellent sample of the most recent advances of CBR in the health sciences.     

微生物亚油酸异构酶的生物信息学分析

运用生物信息学方法,对已在GenBank上公开发表的罗伊氏乳杆菌、疮疱丙酸杆菌、嗜酸乳杆菌、植物乳杆菌和短双岐杆菌等的亚油酸异构酶基因序列进行了分析,并对这些基因序列编码的蛋白质进行了预测.     

SORTAL ANAPHORA RESOLUTION IN MEDLINE ABSTRACTS

This paper reports our investigation of machine learning methods applied to anaphora resolution for biology texts, particularly paper abstracts. Our primary concern is the investigation of features and their combinations for effective anaphora resolution. In this paper, we focus on the resolution of demonstrative phrases and definite determiner phrases, the two most prevalent forms of anaphoric expressions that we find in biology research articles. Different resolution models are developed for demonstrative and definite determiner phrases. Our work shows that models may be optimized differently for each of the phrase types. Also, because a significant number of definite determiner phrases are not anaphoric, we induce a model to detect anaphoricity, i.e., a model that classifies phrases as either anaphoric or nonanaphoric. We propose several novel features that we call highlighting features , and consider their utility particularly for processing paper abstracts. The system using the highlighting features achieved accuracies of 78% and 71% for demonstrative phrases and definite determiner phrases, respectively. The use of the highlighting features reduced the error rate by about 10%.     

桌面网格计算平台在多序列比对算法中的运用

提出了一种多序列比对ClustalW算法并行化处理的新方法ParaClustalW,该方法使用桌面网格计算平台作为高性能编程环境和运行平台.分析了多序列比对算法在桌面网格平台上的任务划分方式、并行化策略和实现技术.ParaClustalW策略考虑到序列的数目与序列的长度等因素,实现任务划分的均衡性.经实验证明,Para...     

An Overview of Synergistic Data Tools for Biological Scrutiny

A network of biological databases is reviewed, supplying a framework for studies of human genes and the association of their genomic variations with human phenotypes. The network is composed of GeneCards, the human gene compendium, which provides comprehensive information on all known and predicted human genes, along with its suite members GeneDecks and GeneLoc. Two databases are shown that address genes and variations focusing on olfactory reception (HORDE) and transduction (GOSdb). In the realm of disease scrutiny, we portray MalaCards, a novel comprehensive database of human diseases and their annotations. Also shown is GeneKid, a tool aimed at generating novel kidney disease biomarkers using systems biology, as well as Xome, a database for whole-exome next-generation DNA sequences for human diseases in the Israeli population. Finally, we show LifeMap Discovery, a database of embryonic development, stem cell research and regenerative medicine, which links to both GeneCards and MalaCards.