Chemical Biology Information Resources

化学生物学信息资源

• 批准号: 8344963
• 负责人: stephen h bryant
• 金额: $ 879.68万
• 依托单位: NATIONAL LIBRARY OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8344963
• 关键词: Affect; Bioinformatics; Biological; Biological Assay; Biological Process; Biological Testing; Biology; Boxing; Chemical Structure; Chemicals; Collection; Data; Databases; Deposition; Discipline; European; Genbank; Gene Proteins; Gene Targeting; Genes; Goals; Individual; Informatics; Information Resources; Institutes; Knock-out; Label; Left; Ligands; Link; Literature; Metabolic; Modeling; Molecular Bank; Names; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Protocols documentation; PubChem; Publications; RNA; Reagent; Records; Reporting; Research; Resources; Scientist; Screening Result; Screening procedure; Source; Specific qualifier value; Standardization; Structure; Systems Biology; Test Result; Toxicology; United States National Institutes of Health; Update; Work; base; chemical binding; conformer; crosslink; high throughput screening; improved; interest; link protein; programs; reagent testing; repository; research study; tautomer; three dimensional structure; tool; transcription factor; usability

PubChem provides a public repository of chemical-structure records contributed by more than 150 organizations. Processing is automated, allowing PubChem's Substance database to grow to over 85 million records in 7 years. A critical aspect of chemical-structure processing is standardization of valence-bond models, to provide the unique tautomer and/or resonance form stored in PubChem's Compound database. Standardization enables cross-linking of deposited Substance records that represent identical chemical structures and calculation of accurate comparison scores to detect compounds with similar though not identical chemical structures. PubChem's chemical structure databases can be searched by chemical name or structure and can display results as NCBI's Entrez document-summary lists, structure similarity diagrams, or detailed Compound and Substance summaries that include relevant biological activity information. An informatics project completed this year calculates multiple theoretical three-dimensional structures for compounds in PubChem. Conformer similarity scores are used as an alternative means to select structurally similar compounds, and in analysis tools that display active-compound and bioactivity similarities among PubChem Bioassays. While accurate enumeration of conformers and selection of stable representatives is possible for chemical structures below a certain complexity, including most in PubChem, theoretical selection of conformers responsible for a given biological activity is most often not possible. An ongoing research and informatics project aims to improve PubChem structure-activity analysis tools by selecting from theoretical ensembles those conformers where conformer-similarity scores are most highly correlated with the experimental bioactivity scores in each PubChem Bioassay. The goal is to provide a chemoinformatics tool that can identify phamacophores, or three-dimensional chemical substructures most associated with bioactivity. PubChem's Bioassay database is a public repository for the results of chemical biology screening experiments, many provided by grantees of the NIH Molecular Libraries Program (MLP). The number of Bioassays has grown this year to over 500 thousand records, containing the results of over 140 million tests of the biological activity of specific chemical reagents. PubChem Bioassays deposited by experimentalists contain a description of experimental protocols and are carefully curated to assure clarity of the experimental readouts provided in the data table associated with each record. Explicit links between Bioassays are created automatically, whenever two Bioassays report test results for one or more of the same reagents, report one or more of the same reagents as biologically active, link to target proteins or genes sequence-similar to one another, and/or link to the same cited publication. Usage of PubChem has also grown this year, to a daily average of over 60,000 users, comparable to other NCBI information resources of interest to scientists in particular disciplines. Informatics projects undertaken this year reflect the growing diversity of bioactivity results reported in PubChem Bioassays. Panel Bioassays that report the activity of tested reagents against many specified targets continue to be used by MLP grantees to demonstrate selectivity of reagents for targets of interest. To accommodate panel Bioassays, new target labels for Bioassay data table readouts were required, as were new readout selections for panel Bioassays related to other Bioassays by target-sequence or reagent-bioactivity similarity. Screens of the biological effects of Small Interfering RiboNucleic Acid (siRNA) reagents that "knock out" expression of individual gene products have also increased. New links to the genes targeted by each reagent were required, as were links to matching siRNA sequences if present in GenBank. Work is in progress to display Bioassay similarity based on siRNA and/or target gene sequence similarity. Another expanded experiment type this year is simplified summary Bioassays, used by MLP grantees to provide an easy-to-update "bottom line" of a multiple-Bioassay screening experiment. To date over 250 summary Bioassays have been deposited. A new source of bioassay results this year has been the contribution of literature-extracted bioactivity experiments by the European Bioinformatics Institute (EBI) ChEMBL project. A total of over 458,000 bioassay records, over 98% of the PubChem total, are now derived from this source. ChEMBL bioassays only report the test results shown in the literature, however, not HTS results as reported by MLP and other experimentalists. So in terms of reported reagent bioactivities, they represent only about 5% of the PubChem total. Other new informatics projects were undertaken to improve the usability and discoverability of PubChem. An important addition this year is the "selected records" box shown to the top-left of all Entrez document-summary lists for PubChem Compound, Substance and Bioassay records. The box summarizes available annotation, such as bioactivity experiments for certain compounds, or protein-target definitions for certain bioassays. The "selected records" box also includes annotation from the new NCBI BioSystems database describing metabolic, transcription-factor, or other systems biology pathways. Each BioSystem record is defined by a description and lists of the molecules forming the pathway, be they protein and/or gene sequences, and/or the chemical structures of metabolites, reagents, or drugs. This annotation in the "selected records" box provides important information on the biological processes affected by a compound, or studied via the gene/protein target of a Bioassay. A similar "selected records" box is shown to the top-left of Entrez document-summary lists for the BioSystems database. This annotates the genes, proteins, and chemical structures forming the over 135,000 BioSystems now included in the collection.

PubChem 提供了由 150 多个组织贡献的化学结构记录的公共存储库。处理是自动化的，使得 PubChem 的物质数据库在 7 年内增长到超过 8500 万条记录。化学结构处理的一个关键方面是价键模型的标准化，以提供存储在 PubChem 化合物数据库中的独特互变异构体和/或共振形式。标准化可以交联代表相同化学结构的存放物质记录，并计算准确的比较分数，以检测具有相似但不相同化学结构的化合物。 PubChem 的化学结构数据库可以按化学名称或结构进行搜索，并且可以将结果显示为 NCBI 的 Entrez 文档摘要列表、结构相似性图或包含相关生物活性信息的详细化合物和物质摘要。 今年完成的一个信息学项目计算了 PubChem 中化合物的多个理论三维结构。构象相似性评分用作选择结构相似化合物的替代方法，并用于显示 PubChem 生物测定中活性化合物和生物活性相似性的分析工具。虽然对于低于一定复杂度的化学结构（包括 PubChem 中的大多数）而言，可以准确计算构象异构体并选择稳定的代表，但对给定生物活性负责的构象异构体的理论选择通常是不可能的。正在进行的研究和信息学项目旨在通过从理论集合中选择那些构象异构体，其中构象异构体相似性得分与每个 PubChem 生物测定中的实验生物活性得分高度相关，来改进 PubChem 结构活性分析工具。目标是提供一种化学信息学工具，可以识别药效团或与生物活性最相关的三维化学子结构。 PubChem 的生物测定数据库是化学生物学筛选实验结果的公共存储库，其中许多由 NIH 分子图书馆计划 (MLP) 的受资助者提供。今年生物测定的数量已增加到超过 50 万条记录，其中包含超过 1.4 亿次特定化学试剂生物活性测试的结果。实验人员存放的 PubChem 生物测定包含实验方案的描述，并经过精心策划，以确保与每条记录相关的数据表中提供的实验读数清晰。当两个生物测定报告一种或多种相同试剂的测试结果、报告一种或多种相同试剂具有生物活性、链接到彼此相似的目标蛋白或基因序列时，生物测定之间的显式链接就会自动创建，并且/或链接到同一引用的出版物。今年 PubChem 的使用量也有所增长，平均每天有超过 60,000 名用户，与特定学科科学家感兴趣的其他 NCBI 信息资源相当。 今年开展的信息学项目反映了 PubChem Bioassays 中报告的生物活性结果日益多样化。 MLP 受资助者继续使用报告测试试剂针对许多特定目标的活性的小组生物测定来证明试剂对感兴趣目标的选择性。为了适应小组生物测定，需要用于生物测定数据表读数的新目标标签，以及通过目标序列或试剂生物活性相似性与其他生物测定相关的小组生物测定的新读数选择。 “敲除”单个基因产物表达的小干扰核糖核酸（siRNA）试剂的生物效应筛选也有所增加。需要与每个试剂靶向的基因建立新的链接，以及与 GenBank 中存在的匹配 siRNA 序列的链接。基于 siRNA 和/或靶基因序列相似性显示生物测定相似性的工作正在进行中。今年另一个扩展的实验类型是简化摘要生物测定，MLP 受资助者使用它来提供易于更新的多重生物测定筛选实验的“底线”。迄今为止，已保存超过 250 个生物测定摘要。今年生物测定结果的一个新来源是欧洲生物信息学研究所 (EBI) ChEMBL 项目文献提取的生物活性实验的贡献。目前共有超过 458,000 条生物测定记录（占 PubChem 总数的 98% 以上）源自此来源。然而，ChEMBL 生物测定仅报告文献中显示的测试结果，而不是 MLP 和其他实验人员报告的 HTS 结果。因此，就报告的试剂生物活性而言，它们仅占 PubChem 总数的 5% 左右。 其他新的信息学项目的开展是为了提高 PubChem 的可用性和可发现性。今年的一个重要补充是“选定记录”框，显示在 PubChem 化合物、物质和生物测定记录的所有 Entrez 文档摘要列表的左上角。该框总结了可用的注释，例如某些化合物的生物活性实验，或某些生物测定的蛋白质靶标定义。 “所选记录”框还包括来自新 NCBI BioSystems 数据库的注释，描述代谢、转录因子或其他系统生物学途径。每个生物系统记录由形成途径的分子的描述和列表定义，无论是蛋白质和/或基因序列，和/或代谢物、试剂或药物的化学结构。 “所选记录”框中的注释提供了有关受化合物影响的生物过程或通过生物测定的基因/蛋白质靶标进行研究的重要信息。 BioSystems 数据库的 Entrez 文档摘要列表的左上角显示了类似的“选定记录”框。这注释了目前包含在集合中的超过 135,000 个生物系统的基因、蛋白质和化学结构。