Mechanisms of small-molecule binding to intrinsically disordered proteins
Mechanisms of small-molecule binding to intrinsically disordered proteins
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DOI：
10.1042/bst20120086
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发表时间：
2012-10-01
影响因子：
3.9
通讯作者：
Michel, Julien
中科院分区：
文献类型：
--
作者：
Cuchillo, Remi;Michel, Julien
IDP（本质无序蛋白）在许多重要的细胞过程（例如信号传导或转录）中发挥着至关重要的作用，并且是多种疾病的有吸引力的治疗靶点。 IDP 相当大的结构灵活性对合理的药物发现方法提出了挑战。因此，迄今为止基于结构的药物设计工作主要集中在抑制 IDP 与其他蛋白质的相互作用，这些蛋白质的结构可以通过传统的生物物理方法来解析。然而，近年来，已经报道了一些小分子在无序状态下与单体 IDP 结合的例子，表明这种方法可能为治疗干预提供新的机会。该策略的进一步发展将极大地受益于对小分子和 IDP 之间分子识别机制的更好理解。本文总结了小分子与无序状态下的三种 IDP 之间相互作用机制的实验和计算研究结果：c-Myc、A beta（淀粉样蛋白 β 肽）和 α-突触核蛋白。
IDPs (intrinsically disordered proteins) play crucial roles in many important cellular processes such as signalling or transcription and are attractive therapeutic targets for several diseases. The considerable structural flexibility of IDPs poses a challenge for rational drug discovery approaches. Consequently, structure-based drug design efforts to date have mostly focused on inhibiting interactions of IDPs with other proteins whose structure can be solved by conventional biophysical methods. Yet, in recent years, several examples of small molecules that bind to monomeric IDPs in their disordered states have been reported, suggesting that this approach may offer new opportunities for therapeutic interventions. Further developments of this strategy will greatly benefit from an improved understanding of molecular recognition mechanisms between small molecules and IDPs. The present article summarizes findings from experimental and computational studies of the mechanisms of interaction between small molecules and three IDPs in their disordered states: c-Myc, A beta (amyloid beta-peptide) and alpha-synuclein.