Drug target identification is a fast-growing field of research in many human diseases. Many strategies have been devised in the post-genomic era to identify new drug targets for infectious diseases. Analysis of protein sequences from different organisms often reveals cases of exon/ORF shuffling in a genome. This results in the fusion of proteins/domains, either in the same genome or that of some other organism, and is termed Rosetta stone sequences. They help link disparate proteins together describing local and global relationships among proteomes. The functional role of proteins is determined mainly by domain-domain interactions and leading to the corresponding signaling mechanism. Putative proteins can be identified as drug targets by re-annotating their functional role through domain-based strategies. This study has utilized a bioinformatics approach to identify the putative proteins that are ideal drug targets for pneumonia infection by re-annotating the proteins through position-specific iterations. The putative proteome of two pneumonia-causing pathogens was analyzed to identify protein domain abundance and versatility among them. Common domains found in both pathogens were identified, and putative proteins containing these domains were re-annotated. Among many druggable protein targets, the re-annotation of EJJ83173 (which contains the GFO_IDH_MocA domain) showed that its probable function is glucose-fructose oxidoreduction. This protein was found to have sufficient interactor proteins and homolog in both pathogens but no homolog in the host (human), indicating it as an ideal drug target. 3D modeling of the protein showed promising model parameters. The model was utilized for virtual screening which revealed several ligands with inhibitory activity. These ligands included molecules documented in traditional Chinese medicine and currently marketed drugs. This novel strategy of drug target identification through domain-based putative protein re-annotation presents a prospect to validate the proposed drug target to confer its utility as a typical protein targeting both pneumonia-causing species studied herewith.

中文翻译：

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肺炎克雷伯菌与肺炎链球菌罗塞塔石事件对比分析用于药物靶点鉴定

药物靶点鉴定是许多人类疾病中快速发展的研究领域。在后基因组时代已经设计了许多策略来确定传染病的新药物靶点。对来自不同生物体的蛋白质序列的分析通常会揭示基因组中外显子/ORF 改组的情况。这导致蛋白质/结构域的融合，无论是在同一基因组中，还是在某些其他生物体的基因组中，并被称为罗塞塔石碑序列。它们有助于将不同的蛋白质联系在一起，描述蛋白质组之间的局部和全局关系。蛋白质的功能作用主要由域-域相互作用决定，并导致相应的信号机制。通过基于域的策略重新注释其功能作用，可以将推定的蛋白质识别为药物靶标。本研究利用生物信息学方法，通过特定位置的迭代对蛋白质进行重新注释，从而确定作为肺炎感染理想药物靶点的假定蛋白质。分析了两种引起肺炎的病原体的假定蛋白质组，以确定它们之间的蛋白质结构域丰度和多功能性。鉴定了在两种病原体中发现的共同域，并重新注释了包含这些域的假定蛋白质。在许多可成药的蛋白质靶标中，EJJ83173（包含 GFO_IDH_MocA 结构域）的重新注释表明其可能的功能是葡萄糖 - 果糖氧化还原。发现这种蛋白质在两种病原体中都具有足够的相互作用蛋白和同源物，但在宿主（人）中没有同源物，表明它是理想的药物靶点。蛋白质的 3D 建模显示出有希望的模型参数。该模型用于虚拟筛选，揭示了几种具有抑制活性的配体。这些配体包括传统中药和目前已上市药物中记载的分子。这种通过基于域的推定蛋白质重新注释来识别药物靶标的新策略为验证所提出的药物靶标提供了前景，以赋予其作为针对本文研究的两种引起肺炎的物种的典型蛋白质的效用。