基于分子对接和药效团的磷脂酶PLA2G1B抑制剂的虚拟筛选

Virtual screening of phospholipase PLA2G1B inhibitors based on molecular docking and pharmacophore

磷脂酶PLA2G1B与饮食诱导肥胖及相关代谢紊乱密切联系,研究表明一些天然类黄酮化合物对磷脂酶有抑制作用.采用整合分子对接和药效团策略筛选PLA2G1B靶向小分子抑制剂.对5种类黄酮化合物与PLA2G1B靶标进行分子模拟对接,分析其相互作用,建立基于配体分子共同特征(HipHop)的药效团模型,应用该模型对ZINC数据库中小分子化合物进行筛选,并对匹配评分良好的化合物进行类药性和药代动力学性质(ADME)预测分析.结果表明,山柰酚、木犀草素、槲皮素、杨梅素和表没食子儿茶素没食子酸酯与PLA2G1B均能较好结合,结合能为-7.17~-6.17 kJ/mol;所构建的药效团模型含有3个氢键供体和1个氢键受体4个特征元素;通过对ZINC数据库中10897个小分子的筛选,共得到722个分子,命中率为6.6%.其中匹配评分>2.5的29个化合物均满足Lipinski规则,大部分化合物的ADME参数良好.研究结果为PLA2G1B抑制剂设计及先导化合物发现提供了参考数据.

Phospholipase PLA2G1B is closely related to diet-induced obesity and related metabolic disorders Studies have shown that some natural flavonoid compounds can inhibit phospholipase.An integrated molecular docking and pharmacophore strategy was used to screen PLA2G1B-targeted small molecule inhibitors.Molecular docking of five flavonoid compounds with PLA2G1B were possessed,and their interaction patterns were analyzed.A pharmacophore model based on common ligand molecular characteristics(HipHop)was established,which was used to screen small molecular compounds from ZINC database.The drug-likeness and pharmacokinetic properties(ADME)of the compounds with good fit values were predicted The results show that kaempferol,luteolin,quercetin,myricetin and epigallocatechin gallate can bind PLA2G1B well,with the binding energies of-7.17~-6.17 kJ/mol.The pharmacophore model consisted of three hydrogen bond donors and one hydrogen bond receptor.By screening 10897 small molecules in ZINC database,a total of 722 molecules with a hit rate of 6.6%were obtained.The 29 compounds with fit values higher than 2.5 are all meeting Lipinski’s rule,and most of the compounds have good ADME parameters.These results can provide reference data for the design of PLA2G1B inhibitors and discovery of lead compounds.