Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, 1060 Carmack Rd., Columbus, OH 43210, USA.
Bioorg Med Chem. 2012 Feb 15;20(4):1434-41. doi: 10.1016/j.bmc.2011.12.062. Epub 2012 Jan 12.
Protein aggregates that accumulate in neurodegenerative diseases are important targets of radiotracer discovery efforts. Although multiple scaffold classes have been reported to bind cross-β sheet structure, their mechanism of binding and their ability to interact selectively with aggregates of varying protein composition are not well understood. Here we take a ligand-based quantitative structure-activity relationship approach to identify descriptors of binding affinity and selectivity for a series of 50 closely related benzothiazole derivatives reported to displace Thioflavin T fluorescent probe from synthetic aggregates composed of β-amyloid peptide and insulin. Using a two-step workflow involving both partial least squares and multiple linear regression methods, compound polarizability and hydrophobicity were identified as tunable mediators of binding selectivity. The correlations also revealed how polarizability could be modulated in neutral compounds having push-pull character. These data suggest that the relative affinity of small molecules for binding sites exposed on aggregate surfaces can be modulated by simple chemical design considerations that are compatible with multiple scaffolds.
在神经退行性疾病中积累的蛋白质聚集体是放射性示踪剂发现工作的重要目标。尽管已经报道了多种支架类化合物能够结合交叉-β片层结构，但它们的结合机制以及与不同蛋白质组成的聚集体选择性相互作用的能力尚不清楚。在这里，我们采用基于配体的定量构效关系方法，确定了一系列 50 种密切相关的苯并噻唑衍生物的结合亲和力和选择性描述符，这些衍生物被报道可以从由β-淀粉样肽和胰岛素组成的合成聚集体中置换 Thioflavin T 荧光探针。使用涉及偏最小二乘和多元线性回归方法的两步工作流程，鉴定了化合物极化率和疏水性是结合选择性的可调调节剂。这些相关性还揭示了如何在具有推拉特性的中性化合物中调节极化率。这些数据表明，小分子对暴露在聚集体表面上的结合位点的相对亲和力可以通过与多种支架兼容的简单化学设计考虑来调节。
