Unified Computation Tools for Natural Products Research

摘要 这项拟议的续订申请的首要目标将是进一步推进正在开发的工具，并 有效地将几种类型的分析数据与生物化验数据和基因组信息集成在一起。这将创建一个 一套强大的工具，可以更快、更准确地识别新分子，减少已知分子的复制，以及 从光谱信息中直接推断生物活动。在当前的支持期内，我们已经取得了 在开发用于有机分子的自动注释和识别的高度有用的工具方面取得了实质性进展， 特别关注天然产品。全球天然产物社会(GNPS)分子网络分析和 知识传播生态系统在全球近160个国家和地区处理了近160,000个工作岗位，有4-6,000个 每月提交新工作，每月访问次数超过200,000次(大多数访问是作为参考图书馆 访问、检查公共数据和社区以前作为超链接共享的工作)，并已成为 用于注释来自不同来源的有机分子的主流工具，特别是在代谢组学中 工作流程。深度学习模型小分子精确识别技术(SMART)公共网站 用于提供基于1H-13C HSQC核磁共振数据的候选结构，于2019年12月上线，已经超过 在50个国家提供3000个工作岗位。本提案中开发的所有工具都将成为该分析生态系统的一部分。四个 为这项拟议的研究活动做出贡献的实验室已经创建了一个开放和综合的团队，该团队将继续 创造性地创新新的信息工具，以增强小分子结构的注释和化学推断 和生物学特性。我们有四个具体目标：1)完成一套新的 和用于天然产品分析的创新工具，并将其作为全球免费可用的资源部署 社区。2)通过利用储存库规模的质量来细化分子的结构表征 光谱信息以及核磁共振数据和基因组输入。3)创建基于智能的新工具 将质谱学和HSQC核磁共振数据整合为新的深度学习系统的输入，目标是 实现对结构的更准确的预测。4)使用深度学习来增强生物活性数据的智能 从而使SMART能够根据光谱特征预测分子的活性。数据还将增加 GNPS数据库中有生物化验结合数据。这些目标的另一个后果将是进一步 将天然产品分析数据数字化，以便它们可用于本文计划的计算工具，如 以及未来的其他工具。完成这四个具体目标将创造新的综合工具，以精确 鉴定新的天然产物结构，并能够推断它们与其他类别的天然产物的结构关系 有机分子及其生物学特性。因此，这些新的信息学工具将具有极大的潜力 加强小分子药物发现过程。

Summary The overarching goal for this proposed renewal application will be to further advance tools that are in development and to effectively integrate several types of analytical data with biological assay data and genomic information. This will create a powerful set of tools for faster and even more accurate identification of new molecules, dereplication of known ones, and to directly infer biological activities from spectroscopic information. In the current period of support, we have made substantial progress in developing highly useful tools for automatic annotations and identifications of organic molecules, specifically focused on natural products. The Global Natural Products Social (GNPS) Molecular Networking analysis and knowledge dissemination ecosystem has processed almost 160,000 jobs in nearly 160 countries worldwide, has 4-6,000 new job submissions per month and is accessed over 200,000 times a month (majority accessions are for reference library access, inspection of public data and previous jobs that the community shares as hyperlinks in papers), and has become a mainstream tool for the annotation of organic molecules deriving from diverse sources, especially in metabolomics workflows. The public website for Small Molecule Accurate Recognition Technology (SMART), a deep learning model for providing candidate structures based on 1H-13C HSQC NMR data, went live in December 2019 and already has over 3000 jobs in 50 countries. All tools developed in this proposal will become part of this analysis ecosystem. The four laboratories contributing to this proposed research activity have created an open and integrated team that is continuing to creatively innovate new informatic tools to enhance small molecule structure annotations and inference of their chemical and biological properties. We have four specific aims: 1) To complete the development and evaluation of a set of new and innovative tools for natural products analysis, and deploy these as freely available resources for the worldwide community. 2) To refine the structural characterization of molecules through leveraging repository scale mass spectral information along with NMR data and genomic inputs. 3) To create a new SMART-based tool that integrates mass spectrometry and HSQC NMR data as the input for a new deep learning system with the goal of achieving more accurate predictions of structure. 4) To use deep learning to enhance SMART with bioactivity data so as to enable SMART to predict activities of molecules based on spectroscopic features. The data will also augment the GNPS database with biological assay binding data. An additional consequence of these goals will be the further digitization of natural products analytical data so that they can be used in the computational tools planned herein, as well as other tools in the future. Completion of these four specific aims will create new integrated tools for the precise identification of new natural product structures, and enable inference of their structural relatedness to other classes of organic molecules and their biological properties. Thus, these new informatic tools will have the potential to greatly enhance the small molecule drug discovery process.