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

3D-QSAR Study for Pyridine Heterocyclic Ring PI3K Inhibitor as Anti-renal Cancer Drug

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(p IC50)]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(Co MFA)和比较分子相似性分析(Co MSIA)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Py MOL V1.5软件设计新的PI3K抑制剂分子,并利用Co MFA和Co MSIA法对其活性进行预测。结果:Co MFA和Co MSIA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Co MFA模型中,立体场和静电场的贡献值分别为56.2%、43.8%;在Co MSIA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p IC50分别为3.211、3.247(Co MFA法)和3.238、3.222(Co MSIA法)。结论:新建Co MFA和Co MSIA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。

OBJECTIVE：To study 3 D-QSAR of pyridine heterocyclic ring PI3 K inhibitor as anti-renal cancer drug,and to provide reference for the design and RD of new anti-renal cancer inhibitors. METHODS：The data of structure and active value（p IC50）of 30 pyridine heterocyclic ring PI3 K inhibitors were collected. After Sybyl-X 1.1 software used for molecular superimposition, Co MFA and Co MSIA model were established to investigate three dimensional field, electrostatic field,hydrophobic field,hydrogen bond donor site and hydrogen bond acceptor field of PI3 K inhibitor molecule. Sybyl-X 1.1 software was used for molecular docking,and the mechanism of PI3 K inhibitor molecule and receptor target protein were analyzed.Py MOL V1.5 software was used to design new PI3 K inhibitor molecules. The activity of inhibitor molecules was predicted with Co MFA and Co MSIA model. RESULTS：The cross validation coefficients of Co MFA and Co MSIA 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 Co MFA model, contributions of three dimensional field and electrostatic field were 56.2% and 43.8%respectively. In Co MSIA 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 PI3 K 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 p IC50 of 2 molecules with higher activity were 3.211,3.247（Co MFA method）and 3.238,3.222（Co MSIA method）. CONCLUSIONS：Established new Co MFA and Co MSIA 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 PI3 K inhibitors have strong hydrogen bonding role with receptor target protein. 3 D-QSAR can provide reference for the design,reconstruction and drug RD of new PI3 K inhibitor molecule.