Large Databases of Small Molecules - Drug Development Tool and Public Resource

小分子大型数据库 - 药物开发工具和公共资源

• 批准号: 8350098
• 负责人: MARC NICKLAUS
• 金额: $ 30.3万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8350098
• 关键词: Algorithms; Area; Biological; Biological Assay; Books; Cactaceae; Cataloging; Catalogs; Characteristics; Chemical Structure; Chemicals; Collaborations; Collection; Computer Assisted; Computer Simulation; Computers; Contracts; Custom; Data; Data Set; Databases; Deposition; Developmental Therapeutics Program; Drug Design; Evaluation; Generations; Goals; Housing; Image; Information Sciences; Internet; Journals; Legal patent; Link; Malignant Neoplasms; Methods; Molecular; Molecular Structure; Nature; Optics; Paper; Process; Property; PubChem; Publications; Reading; Records; Research Personnel; Resources; Sampling; Screening procedure; Services; Structure; Synthesis Chemistry; System; Telephone; Textbooks; Time; United States National Institutes of Health; Update; Vendor; Work; Writing; abstracting; chemical synthesis; design; drug development; improved; journal article; next generation; pharmacophore; programs; small molecule; tool; web based interface; web services; wiki

The principal objective of this project is to make large collections of small molecules available for aiding in drug development, both in-house and publicly, to advance the fields of chemical structure identification and processing and of unique compound identifier generation, as well as to provide free chemoinformatics tools aiding one in dealing with such databases. This project started with posting the information in the Open NCI Database on the CADD Group's public web server, but has moved far beyond this data set. Currently, additional databases are being added to this resource, including large vendor catalogs of compounds that can be acquired for screening. Advanced processing is applied to the data, and powerful searching and display capabilities are being implemented. Current efforts in collaboration with governmental, academic and industrial groups world-wide are underway to greatly enhance the total number and scope of associated calculated properties available in the framework of this project. These efforts are intended to make this a powerful resource in in silico screening and computer-aided drug design. One type of interface to these databases will resemble the Enhanced NCI Database Browser. The nature of the resources currently being developed shall be exemplified by a brief description of this service: The data in this current web service comprise data from NCI's Developmental Therapeutics Program (DTP) and additional information with which we have augmented the DTP data sets. We have subjected the Open NCI Database of about 260,000 compounds to various analyses that help to better understand its characteristics and put it in perspective of other large databases used in computer-aided drug design and chemical information sciences. Various clustering methods have been applied to it to elucidate its diversity, and the results have been compared with those for other databases. The Open NCI Database has been converted into various formats, suitable for further processing including 3D pharmacophore searching. We have also implemented a powerful public search tool for the Open NCI Database with a web interface based on the chemical information toolkit CACTVS. Using just a web browser, the user is able to search about 250,000 structures for more than 600 criteria. We have greatly augmented the original DTP files with numerous additional data fields, be it calculated, predicted or hyperlinked information. These data have also been made available in directly downloadable format. Links to several additional services for further processing have been implemented. An online 3D pharmacophore capability has been built, a capability that is currently unique on the web, as far as we are aware of. Searchable predictions of more than 550 different biological activities, calculated by the program PASS for most of the quarter-million compounds, have been included in the web service (abstract). A more recent service is our Chemical Structure Lookup Service (CSLS), available at http://cactus.nci.nih.gov/lookup. CSLS is essentially a "phone book" for small molecules, allowing the user to quickly find out in which, if any, of over 100 different databases (both public and commercial), comprising more than 74 million entries, their compounds occur. Updates of both the user interface and the structure and data holdings are underway as of the time of this writing, which will push the number of entries in CSLS beyond the 100 million mark. Part of these projects is the downloading, reformatting and evaluation for cancer-related purposes, of the massive set of structure and assay data as deposited in PubChem. A recent addition to our collection of public tools is our Optical Structure Recognition service for molecules, mostly developed by Dr. Igor Filippov. OSRA is a utility designed to convert graphical representations of chemical structures, as they appear in journal articles, patent documents, textbooks, trade magazines etc., into SMILES (Simplified Molecular Input Line Entry Specification - see http://en.wikipedia.org/wiki/SMILES - a computer recognizable molecular structure format. OSRA can read a document in over 90 graphical formats parseable - including GIF, JPEG, PNG, TIFF, PDF, PS etc., and generate the SMILES representation of the molecular structure images encountered within that document. A recent addition to our public chemoinformatics tools and services, the Chemical Identifier Resolver (CIR), developed by Dr. Markus Sitzmann. CIR works as a resolver for different chemical structure identifiers and allows one to convert a given structure identifier into another representation or structure identifier. Among others, our in-house developed NCI/CADD Structure Identifiers as well as the new Standard InChI and InChIKey identifiers are handled by this service. One of its key features is that it is a programmatic interface into the Chemical Structure Database (CSDB) of over 120 million small-molecule records (one of the largest chemical databases in the world) that has been compiled by Dr. Sitzmann. Many additional capabilities continue to be added to this service, which is increasingly being integrated with other web services and chemoinformatics tools world-wide. CIR will also become increasingly important in the area of publications involving chemical structures, as efforts increase to make inclusion of computer-readable representations of all compounds presented in a paper mandatory. Dr. Sitzmann has also very recently completed work on the first, early, beta version of the next generation of the CADD Group's Chemical Structure Lookup Service (CSLS II; http://cactus.nci.nih.gov/TEST/chemical/file). The URL of our public web server is http://cactus.nci.nih.gov. Finally, efforts to implement a new resource for making affordable chemical synthesis of screening samples available to all NIH researchers were successfully concluded. This was realized in the form of an extension of the contract with the company ChemNavigator, now part of Sigma-Aldrich, who have implemented the so-called Semi-Custom Synthesis Online Request System (SCSORS). This resource is being increasingly used in our (and other groups') in silico screening, synthetic chemistry, and sample acquisition projects.

该项目的主要目标是提供大量小分子，以帮助内部和公开的药物开发，以推进化学结构识别和处理以及独特化合物标识符生成领域的发展，并提供免费的化学信息学工具可帮助您处理此类数据库。 该项目始于在 CADD 集团公共网络服务器上的开放 NCI 数据库中发布信息，但已远远超出了该数据集的范围。目前，其他数据库正在添加到该资源中，包括可以获取用于筛选的大型供应商化合物目录。对数据进行先进的处理，并实现强大的搜索和显示功能。目前正在与世界各地的政府、学术和工业团体合作，以大大增加该项目框架中可用的相关计算属性的总数和范围。这些努力旨在使其成为计算机筛选和计算机辅助药物设计的强大资源。这些数据库的一种类型的界面类似于增强型 NCI 数据库浏览器。当前正在开发的资源的性质应通过该服务的简要描述来举例说明：当前网络服务中的数据包括来自 NCI 发展治疗计划 (DTP) 的数据以及我们用来扩充 DTP 数据集的附加信息。我们对包含约 260,000 种化合物的开放式 NCI 数据库进行了各种分析，有助于更好地了解其特征，并将其与计算机辅助药物设计和化学信息科学中使用的其他大型数据库放在一起。人们对其应用了各种聚类方法来阐明其多样性，并将结果与​​其他数据库的结果进行了比较。开放 NCI 数据库已转换为各种格式，适合进一步处理，包括 3D 药效团搜索。我们还为开放 NCI 数据库实施了一个强大的公共搜索工具，其网络界面基于化学信息工具包 CACTVS。只需使用 Web 浏览器，用户就可以搜索约 250,000 个结构，并满足 600 多个条件。我们使用大量附加数据字段（计算、预测或超链接信息）极大地增强了原始 DTP 文件。这些数据也以可直接下载的格式提供。已实现与若干附加服务的链接以供进一步处理。据我们所知，在线 3D 药效团功能已经建立，这是目前网络上独一无二的功能。超过 550 种不同生物活性的可搜索预测，由 PASS 程序对 25 万种化合物中的大多数进行计算，已包含在网络服务中（摘要）。 最近的一项服务是我们的化学结构查找服务 (CSLS)，可从 http://cactus.nci.nih.gov/lookup 获取。 CSLS 本质上是小分子的“电话簿”，允许用户快速找出其化合物存在于 100 多个不同数据库（公共数据库和商业数据库）（包含超过 7400 万个条目）中（如果有的话）。截至撰写本文时，用户界面以及结构和数据持有量的更新正在进行中，这将使 CSLS 中的条目数量突破 1 亿大关。 这些项目的一部分是出于与癌症相关的目的，对 PubChem 中存储的大量结构和分析数据进行下载、重新格式化和评估。 我们的公共工具集中最近添加了分子光学结构识别服务，主要由 Igor Filippov 博士开发。 OSRA 是一个实用程序，旨在将期刊文章、专利文件、教科书、商业杂志等中出现的化学结构的图形表示转换为 SMILES（简化分子输入行输入规范 - 请参阅 http://en.wikipedia.org /wiki/SMILES - OSRA 可以读取 90 多种可解析图形格式的文档 - 包括 GIF、JPEG、PNG、TIFF、PDF、PS 等，并生成该文档中遇到的分子结构图像的 SMILES 表示形式是我们公共化学信息学工具和服务的最新成员，即由 Markus Sitzmann 博士开发的化学标识符解析器 (CIR)，可用作不同化学结构标识符的解析器。一种将给定结构标识符转换为另一种表示形式或结构标识符的方法，其中包括我们内部开发的 NCI/CADD 结构标识符以及新的标准 InChI 和 InChIKey 标识符。通过这项服务。其主要功能之一是它是化学结构数据库 (CSDB) 的编程接口，该数据库包含超过 1.2 亿条小分子记录（世界上最大的化学数据库之一），该数据库由 Sitzmann 博士编制。该服务不断添加许多附加功能，并且越来越多地与全球其他网络服务和化学信息学工具集成。随着强制要求在论文中包含所有化合物的计算机可读表示形式，CIR 在涉及化学结构的出版物领域也将变得越来越重要。 Sitzmann 博士最近还完成了 CADD 集团下一代化学结构查找服务 (CSLS II；http://cactus.nci.nih.gov/TEST/chemical/file) 的第一个早期测试版的工作）。我们公共网络服务器的 URL 是 http://cactus.nci.nih.gov。 最后，为所有 NIH 研究人员提供负担得起的筛选样品化学合成新资源的努力已成功完成。这是通过与 ChemNavigator 公司延长合同的形式实现的，该公司现在是 Sigma-Aldrich 的一部分，该公司实施了所谓的半定制合成在线请求系统 (SCSORS)。该资源越来越多地用于我们（和其他团体）的计算机筛选、合成化学和样品采集项目。