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首页> 外文期刊>Quarterly Reviews of Biophysics >Biophysical and computational fragment-based approaches to targeting protein-protein interactions: Applications in structure-guided drug discovery (Review)
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Biophysical and computational fragment-based approaches to targeting protein-protein interactions: Applications in structure-guided drug discovery (Review)

机译：针对蛋白质-蛋白质相互作用的基于生物物理和计算片段的方法：在结构指导的药物发现中的应用（综述）

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Drug discovery has classically targeted the active sites of enzymes or ligand-binding sites of receptors and ion channels. In an attempt to improve selectivity of drug candidates, modulation of protein-protein interfaces (PPIs) of multiprotein complexes that mediate conformation or colocation of components of cell-regulatory pathways has become a focus of interest. However, PPIs in multiprotein systems continue to pose significant challenges, as they are generally large, flat and poor in distinguishing features, making the design of small molecule antagonists a difficult task. Nevertheless, encouragement has come from the recognition that a few amino acids-so-called hotspots-may contribute the majority of interaction-free energy. The challenges posed by protein-protein interactions have led to a wellspring of creative approaches, including proteomimetics, stapled-helical peptides and a plethora of antibody inspired molecular designs. Here, we review a more generic approach: fragment-based drug discovery. Fragments allow novel areas of chemical space to be explored more efficiently, but the initial hits have low affinity. This means that they will not normally disrupt PPIs, unless they are tethered, an approach that has been pioneered by Wells and co-workers. An alternative fragment-based approach is to stabilise the uncomplexed components of the multiprotein system in solution and employ conventional fragment-based screening. Here, we describe the current knowledge of the structures and properties of protein-protein interactions and the small molecules that can modulate them. We then describe the use of sensitive biophysical methods-nuclear magnetic resonance, X-ray crystallography, surface plasmon resonance, differential scanning fluorimetry or isothermal calorimetry-to screen and validate fragment binding. Fragment hits can subsequently be evolved into larger molecules with higher affinity and potency. These may provide new leads for drug candidates that target protein-protein interactions and have therapeutic value.
机译：药物发现经典地针对酶的活性位点或受体和离子通道的配体结合位点。为了改善候选药物的选择性，介导细胞调节途径组分的构象或共置的多蛋白复合物的蛋白-蛋白界面（PPI）的调节已成为关注的焦点。然而，由于多蛋白系统中的PPI通常较大，平坦且区分特征差，因此它们继续构成重大挑战，这使得小分子拮抗剂的设计成为一项艰巨的任务。但是，人们从认识到一些氨基酸（所谓的热点）可能贡献了大部分无相互作用的能量的角度出发，获得了鼓励。蛋白质-蛋白质相互作用带来的挑战催生了许多创新方法，包括蛋白质组模拟，螺旋钉多肽和大量受抗体启发的分子设计。在这里，我们回顾一种更通用的方法：基于片段的药物发现。片段允许更有效地探索化学空间的新区域，但最初的命中具有较低的亲和力。这意味着，除非被束缚，否则它们通常不会破坏PPI，这是Wells及其同事开创的方法。另一种基于片段的方法是稳定溶液中多蛋白系统的未复杂成分，并采用常规的基于片段的筛选方法。在这里，我们描述了蛋白质-蛋白质相互作用以及可以调节它们的小分子的结构和性质的当前知识。然后，我们描述了使用敏感的生物物理方法（核磁共振，X射线晶体学，表面等离子体共振，差示扫描荧光法或等温量热法）来筛选和验证片段结合。片段命中随后可以进化为具有更高亲和力和效能的更大分子。这些可能为靶向蛋白质-蛋白质相互作用并具有治疗价值的候选药物提供新的线索。

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