Biologically active proteins/regions without stable structure (i.e., intrinsically disordered proteins and regions (IDPs and IDRs)) are commonly found in all proteomes. They have a unique functional repertoire that complements the functionalities of ordered proteins and domains. IDPs/IDRs are multifunctional promiscuous binders capable of folding at interaction with specific binding partners on a template- or context-dependent manner, many of which undergo liquid-liquid phase separation, leading to the formation of membrane-less organelles and biomolecular condensates. Many of them are frequently related to the pathogenesis of various human diseases. All this defines IDPs/IDRs as attractive targets for the development of novel drugs. However, their lack of unique structures, multifunctionality, binding promiscuity, and involvement in unusual modes of action preclude direct use of traditional structure-based drug design approaches for targeting IDPs/IDRs, and make disorder-based drug discovery for these "protein clouds" challenging. Despite all these complexities there is continuing progress in the design of small molecules affecting IDPs/IDRs. This article describes the major structural features of IDPs/IDRs and the peculiarities of the disorder-based functionality. It also discusses the roles of IDPs/IDRs in various pathologies, and shows why the approaches elaborated for finding drugs targeting ordered proteins cannot be directly used for the intrinsic disorder-based drug design, and introduces some novel methodologies suitable for these purposes. Finally, it emphasizes that regardless of their multifunctionality, binding promiscuity, lack of unique structures, and highly dynamic nature, "protein clouds" are principally druggable. Significance Statement Intrinsically disordered proteins and regions are highly abundant in nature, have multiple important biological functions, are commonly involved in the pathogenesis of a multitude of human diseases, and are therefore considered as very attractive drug targets. Although dealing with these unstructured multifunctional protein/regions is a challenging task, multiple innovative approaches have been designed to target them by small molecules.

中文翻译：

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如何给云上药？靶向固有无序的蛋白质。


没有稳定结构的生物活性蛋白质/区域（即固有无序的蛋白质和区域 （IDP 和 IDR））在所有蛋白质组中都很常见。它们具有独特的功能库，可与有序蛋白质和结构域的功能相辅相成。IDP/IDR 是多功能混杂结合物，能够在与特定结合伴侣相互作用时以模板或上下文依赖性方式折叠，其中许多结合伴侣经历液-液相分离，导致形成无膜细胞器和生物分子缩合物。其中许多通常与各种人类疾病的发病机制有关。所有这些都将 IDP/IDR 定义为新药开发的有吸引力的靶点。然而，它们缺乏独特的结构、多功能性、结合混杂性以及参与不寻常的作用模式，因此无法直接使用传统的基于结构的药物设计方法来靶向 IDP/IDR，并使这些“蛋白质云”的基于疾病的药物发现具有挑战性。尽管存在所有这些复杂性，但影响 IDP/IDR 的小分子设计仍在不断取得进展。本文介绍了 IDP/IDR 的主要结构特征以及基于无序的功能的特点。它还讨论了 IDPs/IDRs 在各种病理学中的作用，并说明了为什么为寻找靶向有序蛋白的药物而制定的方法不能直接用于基于内在疾病的药物设计，并介绍了一些适用于这些目的的新方法。最后，它强调，无论它们的多功能性、结合混杂性、缺乏独特结构和高度动态的性质，“蛋白质云”主要是可成药的。 意义声明 固有无序的蛋白质和区域在自然界中高度丰富，具有多种重要的生物学功能，通常参与多种人类疾病的发病机制，因此被认为是非常有吸引力的药物靶点。尽管处理这些非结构化多功能蛋白质/区域是一项具有挑战性的任务，但已经设计了多种创新方法来通过小分子靶向它们。