Over the past decade, there has been a growing interest in investigating whether disordered proteins can be targeted for clinical purposes using small molecules [1-8]. While small-molecule binding to disordered proteins can be seen as unorthodox, examples of this phenomenon have been reported. In order to rationalize these observations, a variety of models are emerging, sometimes in apparent contradiction. Here, we offer a "structural ensemble modulation" view as an attempt to clarify the language, organize concepts, and facilitate the comparison of different studies. In doing so, we hope to promote the understanding of the general principles underlying this phenomenon toward the development of novel therapeutic compounds targeting disordered proteins, which are prevalent in a wide range of human diseases [1-8].
Keywords: disordered proteins; drug discovery; entropy; small molecules; structural ensembles.
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