New Methodologies for Accelerating Natural Product Discovery

描述（由申请人提供）：本申请是对天然产物化学新方法申请请求（RFA-RM-09-005）的回应。我们建议建立一个新的天然产物发现计划，基于a)洞穴衍生微生物形式的新生物来源和b)基于离子迁移质谱（IM-MS）的新分析方法。这两个方面将为发现天然产物开辟新的生物多样性宝库，并提供一种新的方法来加速发现粗提取物中的化合物并减少分离它们所涉及的劳动。由于能够根据IM-MS测量的特性优先考虑代谢物的分离和结构阐明，因此节省了人力和时间。目的1。利用离子迁移率质谱（IM-MS）开发天然产物分析。IM-MS是一种二维质谱法，它可以绘制质量/电荷比和气相碰撞横截面积，这可能与分子的构象和功能直接相关。我们将评估质量碰撞面积比与自然产物类别的相关性，并将这些相关性与计算预测值进行比较。这些数据将化合物的结构、类和构象映射到IM-MS值。目标2。开发洞穴微生物作为天然产物多样性的新来源。可培养的低温粘菌和放线菌的分离、低温保存和基因分类鉴定将为天然产物的发现提供新的储层，并为后续研究提供提取材料。目标3。发展IM-MS作为鉴别提取物中候选物质的方法。一个分类学上独特的生物子集将通过IM-MS评估其次生代谢潜力。具有区分化合物类别、功能或独特构象的IM-MS性质的化合物将成为分离/结构阐明的目标。目标是平行的，但却是协同的。从复杂来源鉴定次生代谢物的新方法对于加速发现是必不可少的。不断需要新的生物多样性来源，以扩大对其生物合成分子多样性的利用。洞穴微生物将为开发IM-MS作为鉴定提取物次生代谢物的工具提供必要的生物来源。通过提出的方法发现的天然产物将提供给NIH分子文库计划（MLP），包括分子文库探针生产中心网络（MLPCN），分子文库小分子库（MLSMR）和PubChem。

DESCRIPTION (provided by applicant): This application is in response to a Request for Applications for New Methodologies in Natural Product Chemistry (RFA-RM-09-005). We propose a campaign to establish a new program of natural product discovery based on a) a new biological source in the form of cave derived microorganisms and b) a new analytical method based on ion mobility mass spectrometry (IM-MS). These two aspects will open up a new reservoir of biodiversity for the discovery of natural products and provide a new method to accelerate the discovery of compounds in crude extracts and reduce the labor involved in their isolation. The labor and time savings derive from the ability to prioritize metabolites for isolation and structure elucidation based on their IM-MS measured properties. Aim 1. Develop natural product analysis using ion mobility mass spectroscopy (IM-MS). IM-MS is a form of 2-dimensional mass spectrometry that plots both mass/charge ratio and gas-phase collision cross- sectional area, which may be directly related to molecular conformation and functionality. We will evaluate the correlation of mass-collision area ratio to natural product class and compare these correlations to computationally predicted values. These data will map compound structure, class and conformation to IM-MS values. Aim 2. Develop cave microorganisms as a new source of natural product diversity. The isolation, cryogenic preservation and genotaxonomic characterization of culturable hypogean myxobacteria and actinobacteria will provide a new reservoir for natural product discovery and a source of extract material for the subsequent aims. Aim 3. Develop IM-MS as a method to identify candidates in extracts. A subset of taxonomically unique organisms will be evaluated for secondary metabolic potential by IM-MS. Compounds with IM-MS properties that distinguish compound class, functionality or unique conformation will be targeted for isolation/structure elucidation. The aims are parallel, but synergistic. New methods for identifying secondary metabolites from complex sources are essential for accelerating discovery. New sources of biodiversity are continuously needed to expand access to their biosynthetic molecular diversity. Cave microorganisms will provide a biological source of extracts needed to develop IM-MS as tool for identification of secondary metabolites in extracts. The natural products discovered by proposed methodologies will be available to the NIH Molecular Libraries Program (MLP) including Molecular Libraries Probe Production Centers Network (MLPCN), Molecular Libraries Small- Molecule Repository (MLSMR) and PubChem. PUBLIC HEALTH RELEVANCE: Natural products are an excellent source for drugs, but they are difficult to discover as they must be identified as minor components of complex extracts from biological sources. We propose to develop two-dimensional separations on the basis of molecular structure and mass to guide the identification of natural products from complex biological sources. Furthermore, cave derived microorganisms, a previously untapped source of biodiversity, will be investigated for natural product discovery.