Abstract:
Human Galectin-3 (hGal-3) is a protein that selectively binds to β-galactosides and holds diverse roles in both normal and pathological circumstances. Therefore, targeting hGal-3 has become a vibrant area of research in the pharmaceutical chemistry. As a step towards the development of novel hGal-3 inhibitors, we synthesized and investigated derivatives of thiodigalactoside (TDG) modified with different aromatic substituents. Specifically, we describe a high-yielding synthetic route of thiodigalactoside (TDG); an optimized procedure for the synthesis of the novel 3,3\'-di-O-(quinoline-2-yl)methyl)-TDG and three other known, symmetric 3,3\'-di-O-TDG derivatives ((naphthalene-2yl)methyl, benzyl, (7-methoxy-2H-1-benzopyran-2-on-4-yl)methyl). In the present study, using competition Saturation Transfer Difference (STD) NMR spectroscopy, we determined the dissociation constant (Kd) of the former three TDG derivatives produced to characterize the strength of the interaction with the target protein (hGal-3). Based on the Kd values determined, the (naphthalen-2-yl)methyl, the (quinolin-2-yl)methyl and the benzyl derivatives bind to hGal-3 94, 30 and 24 times more strongly than TDG. Then, we studied the binding modes of the derivatives in silico by molecular docking calculations. Docking poses similar to the canonical binding modes of well-known hGal-3 inhibitors have been found. However, additional binding forces, cation-π interactions between the arginine residues in the binding pocket of the protein and the aromatic groups of the ligands, have been established as significant features. Our results offer a molecular-level understanding of the varying affinities observed among the synthesized thiodigalactoside derivatives, which can be a key aspect in the future development of more effective ligands of hGal-3.
摘要:
人半乳糖凝集素-3(hGal-3)是一种选择性结合β-半乳糖苷的蛋白质,在正常和病理情况下都具有多种作用。因此,靶向hGal-3已成为药物化学研究的一个充满活力的领域。作为开发新型hGal-3抑制剂的一步,我们合成并研究了用不同的芳族取代基修饰的硫代半乳糖苷(TDG)衍生物。具体来说,我们描述了硫二半乳糖苷(TDG)的高产率合成路线;合成新型3,3'-二-O-(喹啉-2-基)甲基)-TDG和其他三种已知的优化程序,对称3,3'-二-O-TDG衍生物(((萘-2基)甲基,苄基,(7-甲氧基-2H-1-苯并吡喃-2-on-4-基)甲基)。在本研究中,使用竞争饱和转移差(STD)核磁共振波谱,我们测定了所产生的前三种TDG衍生物的解离常数(Kd),以表征与靶蛋白(hGal-3)的相互作用强度。根据确定的Kd值,(萘-2-基)甲基,(喹啉-2-基)甲基和苄基衍生物与hGal-3的结合比TDG强94、30和24倍。然后,我们通过分子对接计算研究了衍生物在计算机上的结合模式。已经发现了类似于众所周知的hGal-3抑制剂的典型结合模式的对接姿势。然而,额外的约束力,蛋白质结合袋中的精氨酸残基与配体的芳香基团之间的阳离子-π相互作用,已被确立为显著特征。我们的结果提供了分子水平的理解,在合成的硫代半乳糖苷衍生物之间观察到的不同的亲和力,这可能是未来开发更有效的hGal-3配体的关键方面。