Department of Environmental Health, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea; Department of Nanobiotechnology and Bioinformatics, University of Sciences and Technology, Daejeon 305-350, Republic of Korea.
Int J Biol Macromol. 2018 Jun;112:686-693. doi: 10.1016/j.ijbiomac.2018.02.026. Epub 2018 Feb 6.
In this study we conducted serial kinetic studies integrated with computational simulations to judge the inhibitory effect of pyrogallol on α-glucosidase, due to the association between this enzyme and the treatment of type 2 diabetes. As a result, we found that pyrogallol bound to the active site of α-glucosidase, interacting with several key residues, such as ASP68, MET69, TYR71, PHE157, PHE158, PHE177, GLN181, HIS348, ASP349, ASP406, VAL407, ASP408, ARG439, and ARG443, which was predicted by performing a protein-ligand docking simulation. Subsequently, we evaluated the inhibitory effect of pyrogallol on α-glucosidase, and found that it induced a mixed type of inhibition in a reversible and quick-binding manner. The relevant kinetic parameters were evaluated to be: IC=0.72±0.051mM; K=0.37±0.018mM. A tertiary conformational change was synchronized with pyrogallol inhibition and modulation of the shape of the active site was correspondingly observed. Our study provides insight into the functional inhibitory role of pyrogallol, which results from its triple-hydroxyl groups interacting with the active site of α-glucosidase. We suggest that compounds similar to pyrogallol (phenolic hydroxyl compounds) which target the key residues of the active site of α-glucosidase could be potential agents for α-glucosidase inhibition.
在这项研究中，我们进行了一系列的动力学研究，并结合计算模拟来判断焦性没食子酸对α-葡萄糖苷酶的抑制作用，因为这种酶与 2 型糖尿病的治疗有关。结果发现，焦性没食子酸与α-葡萄糖苷酶的活性位点结合，与几个关键残基相互作用，如 ASP68、MET69、TYR71、PHE157、PHE158、PHE177、GLN181、HIS348、ASP349、ASP406、VAL407、ASP408、ARG439 和 ARG443，这是通过进行蛋白质-配体对接模拟预测的。随后，我们评估了焦性没食子酸对α-葡萄糖苷酶的抑制作用，发现它以可逆和快速结合的方式诱导了混合类型的抑制。评估了相关的动力学参数：IC=0.72±0.051mM；K=0.37±0.018mM。焦性没食子酸抑制伴随着三级构象的变化，同时观察到活性位点形状的相应调节。我们的研究提供了对焦性没食子酸功能抑制作用的深入了解，这是由于其三个羟基与α-葡萄糖苷酶的活性位点相互作用所致。我们建议，类似焦性没食子酸（酚羟基化合物）的化合物，靶向α-葡萄糖苷酶活性位点的关键残基，可能是α-葡萄糖苷酶抑制的潜在药物。
