Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput in silico screening.
Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput in silico screening.
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DOI：
10.1039/d0sc02159h
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发表时间：
2020-12-21
期刊：
影响因子：
8.4
通讯作者：
Petersson EJ
中科院分区：
文献类型：
--
作者：
Ferrie JJ;Lengyel-Zhand Z;Janssen B;Lougee MG;Giannakoulias S;Hsieh CJ;Pagar VV;Weng CC;Xu H;Graham TJA;Lee VM;Mach RH;Petersson EJ
超高通量计算机筛选鉴定了与α-突触核蛋白原纤维结合的分子，通过光交联、结构-活性研究和放射性配体结合来分析这些分子，以验证这种方法用于寻找成像探针。以高亲和力和特异性结合α-突触核蛋白（αS）蛋白原纤维的小分子有可能作为正电子发射断层扫描（PET）成像探针，以帮助诊断帕金森病和相关的突触核蛋白病。为了鉴定这些分子，我们采用了超高通量的计算机筛选策略，使用理想化的假配体（称为范例）来鉴定用于实验结合研究的化合物。对于此次筛选的热门结果，我们使用光交联来确认其结合位点，并研究其类似物的结构-活性关系，以开发出对αS原纤维具有纳摩尔亲和力且对αS的特异性中等于Aβ原纤维的分子。最后，我们通过使用已鉴定分子的放射性标记类似物测量与小鼠脑组织中富含α S的匀浆的结合，证明了铅类似物作为成像探针的潜力。这项研究证明了我们强大的新方法的有效性，以发现PET探针的挑战性分子靶点。
Ultra-high throughput in silico screening identified molecules that bind to α-synuclein fibrils, which were analyzed by photo-crosslinking, structure-activity studies, and radioligand binding to validate this approach for finding imaging probes. Small molecules that bind with high affinity and specificity to fibrils of the α-synuclein (αS) protein have the potential to serve as positron emission tomography (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such molecules, we employed an ultra-high throughput in silico screening strategy using idealized pseudo-ligands termed exemplars to identify compounds for experimental binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure–activity relationship of its analogs to develop multiple molecules with nanomolar affinity for αS fibrils and moderate specificity for αS over Aβ fibrils. Lastly, we demonstrated the potential of the lead analog as an imaging probe by measuring binding to αS-enriched homogenates from mouse brain tissue using a radiolabeled analog of the identified molecule. This study demonstrates the validity of our powerful new approach to the discovery of PET probes for challenging molecular targets.
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