An approach to enzyme inhibition employing reversible boronate ester formation
An approach to enzyme inhibition employing reversible boronate ester formation
复制标题
DOI：
10.1039/c1md00011j
复制
发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Claridge, Timothy D. W.
中科院分区：
文献类型：
--
作者：
Leung, Ivanhoe K. H.;Brown, Tom, Jr.;Claridge, Timothy D. W.
动态组合化学（DCC）是鉴定生物大分子配体的一种潜在有用的方法；然而，适用于水溶液中 DCC 的反应数量有限。我们报告了使用 α-胰凝乳蛋白酶作为模型系统，研究硼酸与醇的可逆反应作为酶抑制方法的研究。 NMR技术（B-11 NMR和H-1 waterLOGSY）用于观察硼酸、糖和α-胰凝乳蛋白酶的三元复合物，并且可用于区分硼酸和糖的优先结合组合。结果表明，溶液中硼酸酯形成的倾向和硼酸酯对目标酶的亲和力决定是否观察到三元复合物的形成。结果还为 DCC 与蛋白质靶标的硼酸酯方法提供了原理证明。
Dynamic combinatorial chemistry (DCC) is a potentially useful method for the identification of biomacromolecule ligands; however, the number of reactions applicable to DCC in aqueous solution is limited. We report studies that investigate the reversible reaction of boronic acids with alcohols as an approach to enzyme inhibition, employing alpha-chymotrypsin as a model system. NMR techniques (B-11 NMR and H-1 waterLOGSY) were used to observe ternary complexes of boronic acids, sugars and alpha-chymotrypsin, and were useful for distinguishing preferentially binding combinations of boronic acids and sugars. The results reveal that both the propensity of boronate ester formation in solution and affinity of the boronate ester for the target enzyme determine whether ternary complex formation is observed. The results also provide proof of principle for the boronate ester approach to DCC versus protein targets.