抗肾癌药物吡啶杂环类PI3K抑制剂的三维定量构效关系研究 点击下载
论文标题： 抗肾癌药物吡啶杂环类PI3K抑制剂的三维定量构效关系研究
英文标题：
中文摘要： 目的：研究抗肾癌药物吡啶杂环类磷脂酰肌醇3-激酶（PI3K）抑制剂的三维定量构效关系（3D-QSAR），为新型抗肾癌药物的设计与研发提供参考。方法：收集30个吡啶杂环类PI3K抑制剂分子的结构和活性值[即半数抑制浓度的负对数（pIC50）]数据，使用Sybyl-X 1.1软件进行分子叠合后，构建比较分子力场分析（CoMFA）和比较分子相似性分析（CoMSIA）模型，对PI3K抑制剂分子的立体场、静电场、疏水场、氢键供体场和氢键受体场进行考察；使用Sybyl-X 1.1软件进行分子对接，对PI3K抑制剂分子与受体靶标蛋白的作用机制进行分析；使用PyMOL V1.5软件设计新的PI3K抑制剂分子，并利用CoMFA和CoMSIA法对其活性进行预测。结果：CoMFA和CoMSIA模型的交叉验证系数分别为0.617、0.601，拟合验证系数分别为0.969、0.974，外部验证复相关系数分别为0.656、0.670。在CoMFA模型中，立体场和静电场的贡献值分别为56.2％、43.8％；在CoMSIA模型中，立体场、静电场、疏水场、氢键供体场、氢键受体场的贡献值分别为41.0％、31.3％、21.1％、2.4％、4.2％。分子叠合后，在公共骨架R1取代基附近引入空间位阻较小、正电性及亲水性较强的基团均可有助于增强分子活性。分子对接结果显示，PI3K抑制剂分子与受体靶标蛋白中的关键氨基酸ALA805、VAL882、THR887共形成了3个氢键，长度分别为1.84、1.99、1.99 ?。根据上述信息共设计了6个新分子，其中2个活性较高的分子的预测pIC50分别为3.211、3.247（CoMFA法）和3.238、3.222（CoMSIA法）。结论：新建CoMFA和CoMSIA模型具有良好的预测能力和统计学稳定性。分子立体场对分子活性的贡献值大于静电场，同时疏水场对分子活性的影响也不容忽视。吡啶杂环类PI3K抑制剂与受体靶标蛋白具有较强的氢键作用。3D-QSAR可为后续新的PI3K抑制剂分子的设计、改造及药物研发提供参考。
英文摘要： OBJECTIVE： To study 3D-QSAR of pyridine heterocyclic ring PI3K inhibitor as anti-renal cancer drug， and to provide reference for the design and R&D of new anti-renal cancer inhibitors. METHODS： The data of structure and active value （pIC50） of 30 pyridine heterocyclic ring PI3K inhibitors were collected. After Sybyl-X 1.1 software used for molecular superimposition， CoMFA and CoMSIA model were established to investigate three dimensional field， electrostatic field， hydrophobic field， hydrogen bond donor site and hydrogen bond acceptor field of PI3K inhibitor molecule. Sybyl-X 1.1 software was used for molecular docking， and the mechanism of PI3K inhibitor molecule and receptor target protein were analyzed. PyMOL V1.5 software was used to design new PI3K inhibitor molecules. The activity of inhibitor molecules was predicted with CoMFA and CoMSIA model. RESULTS： The cross validation coefficients of CoMFA and CoMSIA model were 0.617 and 0.601， fitting validation coefficients were 0.969 and 0.974， and external predictive correlation coefficients were 0.656 and 0.670， respectively. In CoMFA model， contributions of three dimensional field and electrostatic field were 56.2％ and 43.8％ respectively. In CoMSIA model， contributions of three dimensional field， electrostatic field， hydrophobic field， hydrogen bond donor site and hydrogen bond acceptor field were 41.0％， 31.3％， 21.1％， 2.4％， 4.2％. After molecular superimposition， small steric hindrance， strong positive and hydrophilic groups introduced nearby R1 group of common skeleton could help to enhance the activity of molecules. The results of molecular docking showed that PI3K inhibitor molecule formed three hydrogen bonds with the key amino acids ALA805， VAL882 and THR887 of receptor target protein， with the length of 1.84，1.99，1.99 ?. According to above information， 6 new molecules were designed， among which predicted pIC50 of 2 molecules with higher activity were 3.211， 3.247 （CoMFA method） and 3.238， 3.222 （CoMSIA method）. CONCLUSIONS： Established new CoMFA and CoMSIA model have good prediction ability and statistical stability. Contribution of three dimensional field is higher than that of electrostatic field， and the influence of hydrophobic field on molecular activity can not be ignored. Pyridine heterocyclic ring PI3K inhibitors have strong hydrogen bonding role with receptor target protein. 3D-QSAR can provide reference for the design， reconstruction and drug R&D of new PI3K inhibitor molecule.
期刊： 2018年第29卷第12期
作者： 刘桦，蒲铃铃，宋海星，尹小菲，梁桂兆
英文作者： LIU Hua，PU Lingling，SONG Haixing，YIN Xiaofei，LIANG Guizhao
关键字： 磷脂酰肌醇3-激酶抑制剂；三维定量构效关系；比较分子力场分析；比较分子相似性分析
KEYWORDS： PI3K inhibitor； 3D-QSAR； CoMFA； CoMSIA
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