For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls—hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested.

中文翻译：

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弱微生物代谢物：利用仿生学发现和优化药物的宝库。


几十年来，传统的药物发现一直使用天然产物和合成化学方法来生成化合物库，其中一些最终成为有前途的候选药物。一种补充方法是采用天然产物和代谢物的仿生学概念，以改善母体分子的多种药物样特征。在这一努力中，配体和受体之间混杂且微弱的相互作用在药物发现过程中经常被忽略。在这篇新兴概念文章中，我们重点介绍了微生物代谢物拟态，即母体代谢物与其受体具有微弱的相互作用，从而产生了更有效的药物样分子的离散例子。我们展示了在体外和体内具有有效作用的母体代谢物模拟物的具体例子。此外，我们展示了新兴的微生物配体-受体相互作用的例子，并提供了这些配体可以作为潜在药物进行改进的背景。提供了一个平衡的概念进展，其中我们也承认潜在的陷阱——精细平衡的受体-配体相互作用的过度刺激也可能是有害的。然而，为了平衡，我们提供了一些例子来说明这个新兴概念需要在哪里进行测试。