雷洛昔芬
化学
生物信息学
虚拟筛选
丙氨酸扫描
药物重新定位
对接(动物)
重新调整用途
药品
药物发现
生物化学
计算生物学
丙氨酸
药效团
药理学
氨基酸
突变
雌激素受体
突变
生物
遗传学
护理部
癌症
乳腺癌
基因
生态学
医学
作者
Jiaofeng Wu,Baichun Hu,Shuaizhong Lu,Rong Duan,Haoran Deng,Lele Li,He Li,Yunli Zhao,Jian Wang
标识
DOI:10.1016/j.carres.2021.108478
摘要
α-Glucosidase is a promising target for the treatment of diabetes. Drug repurposing can increase the chances of discovering an active inhibitor. Therefore, this study aimed to identify potential α-glucosidase inhibitor using drug repurposing and in silico strategies. We identified critical amino acid residues of the three α-glucosidase proteins. Based on cross molecular docking studies of three α-glucosidase proteins and drugs in the FDA database, we screened hits with the favorable binding affinities and modes targeting the three proteins. Subsequently, an in vitro activity assay showed that raloxifene was an excellent inhibitor of α-glucosidase. Moreover, molecular dynamics simulations of raloxifene and three proteins were performed to assess the stability of the protein-hit systems in physiological conditions and clarify protein-hit interactions. We also performed the binding free energy calculation, Hirshfeld surface and alanine scanning mutagenesis analyses. These results demonstrated that binding between raloxifene and the three proteins was stable, and the critical amino acid residues of the three proteins formed stable contacts with raloxifene. The molecular mechanisms agree well with its activity, reinforcing that raloxifene is a candidate α-glucosidase inhibitor. Our study smoothes the path for the development of novel a-glucosidase inhibitors with high efficacy and low toxicity for the treatment of diabetes.
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