2018年第45卷第4期目录
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封面故事:蛋白酪氨酸磷酸酶1B (PTP1B) 是治疗Ⅱ型糖尿病的新型靶点之一,筛选天然产物来源的PTP1B抑制剂有助于开发糖尿病治疗新药.本文构建了含有42 296个小分子的天然产物库,以PTP1B蛋白为靶标,采用基于分子对接的虚拟筛选方法并结合ADMET性质预测,从所构建的天然产物库中筛选出类药性良好的三个化合物,包括对苯醌类化合物7、烷基异香豆素类衍生物10和Clavepictine类似物11,其中化合物10和11的PTP1B抑制活性未见报道.结合方式分析表明,化合物7和11主要通过氢键与PTP1B结合,占据其第一位点;化合物10通过5个氢键、1个π-σ键、疏水作用、范德华力和静电相互作用与PTP1B结合,既占据第一位点又占据第二位点,还与WPD环和连接处结合,推测有较强的抑制活性和选择性.体外抑制实验证明,化合物10对PTP1B的IC50为(74.58 ± 1.23) μmol/L,抑制活性良好.
(张 倩,甘 强,刘 霞,陈 曦,冯长根.基于天然产物的蛋白酪氨酸磷酸酶1B抑制剂的虚拟筛选,本期第442~452页)
Cover Story:Protein tyrosine phosphatase 1B (PTP1B) is one of the targets of type Ⅱ diabetes, screening PTP1B inhibitors is of great significance. Structure-based virtual screening against a library of natural products containing 42 296 molecules was conducted to determine the occurrence of PTP1B inhibitors by molecular docking method. Firstly, the active sites of PTP1B complex crystal structure (PDB code: 1XBO) were analyzed and 7 amino acid residues, Arg254,Gln262,Tyr46,Asp181,Ser216,Phe182,and Arg221, were identified as the active pocket. Before docking, all the molecules were filtered according to the Lipinski’s Rule of Five. Then, the screening was carried out based on the LibDock module and CDOCKER module, and 11 top-scored compounds were screened out as virtual hits. Of which 3 molecules, namely para-benzoquinone compound 7, isocoumarins derivative 10 and Clavepictine analogue 11, were determined with low toxicity ultimately according to the predictive ADME simulation and predictive toxic simulation. Binding model analysis revealed that these 3 candidate compounds are all good drug-like PTP1B inhibitors, of which the PTP1B inhibitory activity of compound 10 and 11 haven’t been reported before, of which in vitro PTP1B enzyme inhibition of compound 10 was tested with IC50 values of (74.58±1.23) μmol/L, which is potential for the treatment of type Ⅱ diabete.
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综述与专论
研究报告
技术与方法
前沿透视
Letter to Editor
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