The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014–2023) focusing on molecular glues (MGs)—monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them. We classify the compounds in three main categories: degradative MGs, non-degradative MGs or PPI stabilizers, and MGs that induce self-association. Diverse, illustrative examples with structural data are described in detail, emphasizing the elements of molecular recognition and cooperative binding at the interface that are fundamental for a MG mechanism of action.

蛋白质与小分子相互作用的调节是药物发现中发展最快的领域之一。在这篇综述中，我们讨论了过去十年（2014-2023）的进展，重点是分子胶（MG）——通过稳定天然相互作用或诱导新形态相互作用来诱导接近的单价小分子。我们包括偶然的和理性的发现，并描述了用于识别它们的不同方法。我们将化合物分为三大类：降解性 MG、非降解性 MG 或 PPI 稳定剂以及诱导自缔合的 MG。详细描述了具有结构数据的各种说明性示例，强调了分子识别和界面处协同结合的要素，这是 MG 作用机制的基础。