G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Vladivostok 690022, Russian Federation.
Environ Sci Process Impacts. 2019 Oct 16;21(10):1754-1763. doi: 10.1039/c9em00301k.
An integrated in vitro and in silico approach was applied to evaluate the potency of hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and spongiadioxins (OH-PBDDs) isolated from Dysidea sponges on the activity of the recombinant α-d-galactosidase of the GH36 family. It was revealed for the first time that all compounds rapidly and apparently irreversibly inhibited the bacterial α-d-galactosidase. The structure-activity relationship study in the series of OH-PBDEs showed that the presence of an additional hydroxyl group in 5 significantly enhanced the potency (IC50 4.26 μM); the increase of bromination in compounds from 1 to 3 increased their potency (IC50 41.8, 36.0, and 16.0 μM, respectively); the presence of a methoxy group decreased the potency (4, IC50 60.5 μM). Spongiadioxins 6, 7, and 8 (IC50 16.6, 33.1, and 28.6 μM, respectively) exhibited inhibitory action comparable to that of monohydroxylated diphenyl ethers 1-3. Docking analysis revealed that all compounds bind in a pocket close to the catalytic amino acid residues. Molecular docking detected significant compound-enzyme interactions in the binding sites of α-d-galactosidase. Superimposition of the enzyme-substrate and the enzyme-inhibitor complexes showed that their binding sites overlap.
采用体内和体外相结合的方法来评估从海绵 Dysidea 中分离得到的羟基多溴二苯醚（OH-PBDEs）和海绵二噁英（OH-PBDDs）对 GH36 家族重组α-d-半乳糖苷酶活性的影响。这是首次发现所有化合物均能快速且明显不可逆地抑制细菌α-d-半乳糖苷酶。在 OH-PBDE 系列化合物中进行的构效关系研究表明，在 5 位上增加一个额外的羟基可显著增强其活性（IC50 为 4.26 μM）；在化合物 1 至 3 中溴化程度的增加提高了其活性（IC50 分别为 41.8、36.0 和 16.0 μM）；而甲氧基的存在降低了其活性（IC50 为 60.5 μM）。海绵二噁英 6、7 和 8（IC50 分别为 16.6、33.1 和 28.6 μM）的抑制作用与单羟基化二苯醚 1-3 相当。对接分析表明，所有化合物均与靠近催化氨基酸残基的口袋结合。分子对接检测到α-d-半乳糖苷酶结合部位的化合物与酶的显著相互作用。酶-底物和酶-抑制剂复合物的叠加表明它们的结合部位重叠。
