端锚聚合酶抑制剂的作用方式以及药效团模型的构建

Action mode and construction of pharmacophore model of tankyrase inhibitor

为了深入了解端锚聚合酶抑制剂的作用模式,选取15个活性端锚聚合酶抑制剂组成训练集,构建基于配体共同特征的药效团,选取11个活性抑制剂和6个非活性抑制剂组成测试集验证药效团.利用分子对接方法,将15种活性抑制剂对接于端锚聚合酶的腺苷活性口袋中,探究活性抑制剂与端锚聚合酶结合口袋处的关键作用方式.将分子对接结果与药效团模型相结合,构建更精确的药效团模型.基于配体共同特征的药效团模型有5个化学特征,即包含1个芳香环(R)、2个疏水基团(H)和2个氢受体(A).分子对接结果显示,活性抑制剂在腺苷结合口袋处与关键氨基酸的Tyr 1213、Asp 1198和Gly 1196形成氢键.将分子对接结果与药效团模型结合,构建出一个精确的药效团模型(RRHHAAD),在该药效团中,3个氢键分布在腺苷口袋的A和C位点处,2个共轭环(R1和R2)分别与端锚聚合酶的Phe 1188和His 1201形成共轭作用,药效团模型中心的疏水特征(H2)位于B位点处.叠加后得到的药效团可以准确反映腺苷位点的特征,也可以解释抑制剂与端锚聚合酶的互作方式.

In order to further understand the action mode of tankyrase inhibitors,15 active tankyrase inhibitors were adopted to form training set to construct pharmacophore based on the common characteristics of ligands,and 11 active tankyrase inhibitors and six inactive inhibitors were adopted to form test set to validate pharmacophore.15 active tankyrase inhibitors were docked into the binding pocket of tankyrase using molecular docking methods to explore the critical interaction of active inhibitors with the binding pocket.The accurate pharmacophore model was constructed by combining the results of molecular docking with the pharmacophore model.The pharmacophore model based on the common feature of ligands contains five characteristics,including one aromatic ring(R),two hydrophobic groups(H)and two hydrogen receptors(A).The docking results showed that the active inhibitors formed hydrogen bonds with critical amino acids Tyr 1213,Asp 1198 and Gly 1196 at the binding pocket.Finally,an accurate pharmacophore model(RRHHAAD)was constructed by combining the docking simulation with the pharmacophore model.The model contains seven characteristics:there are three hydrogen bonds at sites A and C of adenosine pocket,two conjugated rings(R1 and R2)which can seperately conjugate to Phe 1188 and His 1201 of tankyrase,and one hydrophobicity(H2)at site B of the center of pharmacophore model.The resultant pharmacophore can accurately reflect the characteristics of adenosine sites and explain the interaction between inhibitors and tankyrase.