Molecular Basis of Small-Molecule Binding to α-Synuclein.
Molecular Basis of Small-Molecule Binding to α-Synuclein.
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DOI：
10.1021/jacs.1c07591
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发表时间：
2022-02-16
影响因子：
15
通讯作者：
Shaw DE
中科院分区：
文献类型：
--
作者：
Robustelli P;Ibanez-de-Opakua A;Campbell-Bezat C;Giordanetto F;Becker S;Zweckstetter M;Pan AC;Shaw DE
内源性无序蛋白（IDP）与许多人类疾病有关。然而，它们通常不适合常规的基于结构的药物设计，因为它们固有的构象可变性已经排除了它们与小分子结合的原子水平的理解。在这里，我们提出了长时间尺度，原子水平的分子动力学（MD）模拟单体α-突触核蛋白（IDP，其聚集与帕金森病相关）结合的小分子药物法舒地尔，其中观察到的蛋白质-配体相互作用被发现是在良好的协议与以前报道的NMR化学位移数据。在我们的模拟中，法舒地尔在结合时有利于α-突触核蛋白C末端附近的某些电荷-电荷和π堆积相互作用，但往往不会同时形成这些相互作用，而是破坏其中一种相互作用并在附近形成另一种相互作用（我们称之为动态穿梭机制）。进一步的模拟与小分子选择修改这些相互作用产生的结合亲和力和关键结构特征的结合与随后的NMR实验一致，这表明潜在的MD为基础的策略，以促进合理的设计与无序蛋白质结合的小分子。
Intrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-time-scale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein–ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge–charge and π-stacking interactions near the C terminus of α-synuclein but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.
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影响因子：
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作者：
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通讯作者：
De Fabritiis, Gianni
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作者：
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通讯作者：
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