Guaitoli Valentina, Alvarez-Ginarte Yoanna María, Montero-Cabrera Luis Alberto, Bencomo-Martínez Alberto, Badel Yoana Pérez, Giorgetti Alejandro, Suku Eda
Laboratory of Theoretical and Computational Chemistry, Faculty of Chemistry, Universidad de La Habana, 10400, La Habana, Cuba.
Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA.
J Mol Model. 2020 Aug 4;26(8):222. doi: 10.1007/s00894-020-04470-w.
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.
我们采用了一种全面的计算策略，以了解并最终预测33种1,3 - 二取代咪唑[1,5 - α]吡嗪衍生物的构效关系，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，抑制效力与摩尔体积、一个空间描述符以及药效团中原子C1（q1）和N4（q4）上的净电荷计算值相关，所有这些似乎都对抑制活性有正向贡献。根据实验值和计算值，最有效的化合物将是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）。对接用于推测参与ATP竞争性抑制活性的重要残基。使用改进的线性相互作用能（LIE）方法通过200纳秒的分子动力学（MD）模拟对其进行了验证。通过对接对先前优选结构进行的MD模拟表明，最有效的配体可以与受体的ATP结合位点形成氢键，并且Ser979和Ser1059残基对化合物23的结合稳定性有有利贡献。MD模拟还提供了关于化合物23的化学结构能够适配到ATP结合口袋中的论据，预计在整个模拟过程中其在口袋中保持稳定，并使我们能够暗示静电和疏水相互作用对配体 - 受体复合物稳定性预期会有显著贡献。这里描述的这种计算组合策略可能代表了一种有用且有效的初步方法，以指导将酪氨酸激酶抑制剂鉴定为新的先导化合物。
