We followed a comprehensive computational strategy to understand and eventually predict the structure-activity relationship of thirty-three 1,3-disubstituted imidazole [1,5-α] pyrazine derivatives described as ATP competitive inhibitors of the IGF-1 receptor related to Ewing sarcoma. The quantitative structure-activity relationship model showed that the inhibitory potency is correlated with the molar volume, a steric descriptor and the net charge calculated value on atom C1 (q1) and N4 (q4) of the pharmacophore, all of them appearing to give a positive contribution to the inhibitory activity. According to experimental and calculated values, the most potent compound would be 3-[4-(azetidin-2-ylmethyl) cyclohexyl]-1-[3-(benzyloxy) phenyl] imidazo [1,5-α]pyrazin-8-amine (compound 23). Docking was used to guess important residues involved in the ATP-competitive inhibitory activity. It was validated by 200 ns of molecular dynamics (MD) simulation using improved linear interaction energy (LIE) method. MD of previously preferred structures by docking shows that the most potent ligand could establish hydrogen bonds with the ATP-binding site of the receptor, and the Ser979 and Ser1059 residues contribute favourably to the binding stability of compound 23. MD simulation also gave arguments about the chemical structure of the compound 23 being able to fit in the ATP-binding pocket, expecting to remain stable into it during the entire simulation and allowing us to hint the significant contribution expected to be given by electrostatic and hydrophobic interactions to the ligand-receptor complex stability. This computational combined strategy here described could represent a useful and effective prime approach to guide the identification of tyrosine kinase inhibitors as new lead compounds.

中文翻译：

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一种计算策略，用于了解被描述为与尤文肉瘤相关的IGF-1受体的ATP竞争性抑制剂的1,3-二取代的咪唑[1,5-α]吡嗪衍生物的构效关系。

我们遵循了一种综合的计算策略，以理解并最终预测33种1,3,2-取代的咪唑[1,5-α]吡嗪衍生物的结构-活性关系，这些衍生物被描述为与尤因肉瘤相关的IGF-1受体的ATP竞争性抑制剂。定量构效关系模型表明，抑制力与药效团团的原子C1（q1）和N4（q4）的摩尔体积，空间描述符和净电荷计算值相关，所有这些似乎都给出了对抑制活性的积极贡献。根据实验和计算值，最有效的化合物是3- [4-（氮杂环丁烷-2-基甲基）环己基] -1- [3-（苄氧基）苯基]咪唑[1,5-α]吡嗪-8-胺（化合物23）。对接用于猜测与ATP竞争性抑制活性有关的重要残基。使用改进的线性相互作用能（LIE）方法，通过200 ns的分子动力学（MD）模拟验证了该方法。通过对接的先前优选结构的MD显示，最有效的配体可以与受体的ATP结合位点建立氢键，Ser979和Ser1059残基有利于化合物23的结合稳定性。MD模拟也对化合物23的化学结构提出了质疑能够装配到ATP结合袋中，期望在整个模拟过程中保持稳定，并允许我们暗示静电和疏水相互作用对配体-受体复合物稳定性的重要贡献。这里描述的这种计算组合策略可以代表一种有用和有效的主要方法，以指导酪氨酸激酶抑制剂作为新的先导化合物的鉴定。