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首页> 外文期刊>RSC Advances >Aromatic heterocycle galectin-1 interactions for selective single-digit nM affinity ligands
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Aromatic heterocycle galectin-1 interactions for selective single-digit nM affinity ligands

机译：选择性一位nM亲和配体的芳香杂环半乳糖凝集素-1相互作用

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摘要

A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1. Initial studies on the 3-triazole-thiogalactosides indicated that five membered heterocycles in general gave increased affinity for galectin-1 and improved selectivity over galectin-3. The selectivity profile was similar for thiodigalactosides exemplified by 3,3′ substituted thien-3-yltriazole and thiazol-2-yltriazole, both having single-digit nM galectin-1 affinity and almost 10-fold galectin-1 selectivity. The binding interactions of a thiodigalactoside based galectin-1 inhibitor with two thien-3-yltriazole moieties were studied with X-ray crystallography. One of the thiophene moieties was positioned deeper into the pocket than previously reported phenyltriazoles and formed close contacts with Val31, Ser29, Gly124, and Asp123. The affinity and structural analysis thus revealed that steric and electronic optimization of five-membered aromatic heterocycle binding in a narrow galectin-1 subsite confers high affinity and selectivity.
机译：发现一系列在C-4三唑位置被不同的五元杂环取代的3-三唑-硫代半乳糖苷和3,3'-三唑-硫代二乳糖苷对半乳凝素-1具有高选择性。对3-三唑-硫代半乳糖苷的初步研究表明，五元杂环通常比galectin-3具有更高的对galectin-1的亲和力和更高的选择性。对于硫代二糖半乳糖苷的选择性概况相似，以3，3'取代的噻吩-3-基三唑和噻唑-2-基三唑为例，它们都具有一位数的nM半乳凝素-1亲和力和近半数半乳凝素-1选择性。用X-射线晶体学研究了基于硫代二乙二糖苷的半乳凝素-1抑制剂与两个噻吩-3-基三唑部分的结合相互作用。噻吩部分之一比以前报道的苯基三唑位于口袋中的位置更深，并与Val31，Ser29，Gly124和Asp123形成紧密接触。因此，亲和力和结构分析表明，在狭窄的galectin-1子位点中，五元芳香族杂环的空间和电子优化具有较高的亲和力和选择性。

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