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目的为开发生物活性高、靶位点专一的新型抗弓形虫病药物先导物,以弓形虫毒力决定因子Rop18为药物靶标,在已构建的激酶抑制剂数据库中虚拟筛选小分子抑制剂。方法Rop18激酶结构域的三维晶体结构下载后经MOE软件预处理,46 741种已公开的激酶抑制剂2D结构在ChEMBLdb数据库下载后,通过构象导入搜索化合物优势构象,转换成3D结构。经氨基酸互作和表面电势分析选择合适的抑制剂结合口袋,采用基于配体的药效团构建模式确定靶向配体结合口袋的药效团特征,在构建的数据库中虚拟筛选小分子抑制剂,对符合条件的小分子通过分子对接进行选择和互作模式分析。结果成功构建了包括46 741个已知激酶抑制剂3D结构的数据库,确定了以Rop18的ATP结合口袋作为配体结合位点,构建了保守性药效团模型,模型包括4个氢键受体、1个氢键供体、2个芳香性特征和1个阳离子基团特征,用该药效团在已知激酶抑制剂数据库中共筛选到2 000个符合条件的小分子,经分子对接和打分后,7种小分子被选为具有代表性构型的先导物。结论基于Rop18激酶结构域的三维晶体结构,构建了靶向ATP-结合口袋的药效团模型,筛选得到7种已知的激酶抑制剂,为开发新型抗弓形虫病药物先导化合物提供了具有代表性的分子构型。
OBJECTIVE To develop a novel anti-toxoplasma drug leader with high biological activity and specific target site, a small molecule inhibitor was screened in the constructed kinase inhibitor database using the toxoplasma virulence determinant Rop18 as a drug target. Methods Three-dimensional crystal structure of Rop18 kinase domain was downloaded and pretreated by MOE software. 46 741 known 2D structures of kinase inhibitor were downloaded from ChEMBLdb database, and the dominant conformation of the compound was detected by conformational import and converted into 3D structure. The amino acid interaction and surface potential analysis to select the appropriate inhibitor binding pocket, ligand-based pharmacophore construction mode to determine the characteristics of the targeting ligand binding pocket pharmacophore, in the construction of a virtual screening of small molecule inhibitors , To meet the requirements of small molecules docking through molecular docking and interaction mode analysis. Results A database of 46 741 3D structures of known kinase inhibitors was successfully constructed and a conserved pharmacophore model was constructed using the ATP binding pocket of Rop18 as the ligand binding site. The model includes four hydrogen bond acceptors , 1 hydrogen bond donor, 2 aromatic character and 1 cationic group. A total of 2 000 small molecules that meet the requirements were screened by the pharmacophore in the known kinase inhibitor database. The molecular docking and scoring Seven small molecules were chosen as precursors of a representative configuration. Conclusion Based on the three-dimensional crystal structure of the Rop18 kinase domain, a pharmacophore model targeting ATP-binding pocket was constructed and seven known kinase inhibitors were screened out to provide a representative for the development of a novel anti-toxoplasma drug lead compound Sexual molecular configuration.