Huang Tonghui, Sun Jie, Zhou Shanshan, Gao Jian, Liu Yi
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
Int J Mol Sci. 2017 Jun 30;18(7):1408. doi: 10.3390/ijms18071408.
Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of energy metabolism and has been targeted for drug development of therapeutic intervention in Type II diabetes and related diseases. Recently, there has been renewed interest in the development of direct β1-selective AMPK activators to treat patients with diabetic nephropathy. To investigate the details of AMPK domain structure, sequence alignment and structural comparison were used to identify the key amino acids involved in the interaction with activators and the structure difference between β1 and β2 subunits. Additionally, a series of potential β1-selective AMPK activators were identified by virtual screening using molecular docking. The retrieved hits were filtered on the basis of Lipinski's rule of five and drug-likeness. Finally, 12 novel compounds with diverse scaffolds were obtained as potential starting points for the design of direct β1-selective AMPK activators.
单磷酸腺苷激活蛋白激酶（AMPK）在能量代谢调节中起关键作用，一直是II型糖尿病及相关疾病治疗干预药物开发的靶点。最近，人们对开发直接的β1选择性AMPK激活剂以治疗糖尿病肾病患者重新产生了兴趣。为了研究AMPK结构域结构的细节，通过序列比对和结构比较来确定与激活剂相互作用的关键氨基酸以及β1和β2亚基之间的结构差异。此外，通过分子对接虚拟筛选鉴定了一系列潜在的β1选择性AMPK激活剂。根据Lipinski的五规则和类药性对检索到的命中物进行筛选。最后，获得了12种具有不同骨架的新型化合物，作为设计直接β1选择性AMPK激活剂的潜在起点。
