基于分子对接方法从天然产物数据库中筛选松材线虫的乙酰胆碱脂酶抑制剂

Virtual Screening of Bursaphelenchus xylophilus AChE Inhibitors Based on Molecular Docking from the Natural Products Database

摘要: 目的：运用相似性筛选、分子对接筛选方法联合分子动力学模拟技术从天然产物数据库中挖掘松材线虫乙酰胆碱脂酶(Acetylcholinesterase, AChE)抑制剂。方法：运用同源建模技术构建松材线虫乙酰胆碱脂酶AChE的蛋白质结构，并将已知抑制活性的鱼藤酮作为AChE的配体小分子以获得最佳对接参数及对接网格大小。利用结构相似性筛选、类药性评价、分子对接、分子动力学模拟及结合自由能计算等多种策略，从天然产物数据库中筛选AChE抑制剂。结果：经过多轮筛选，共获得21个命中分子，其中前2位最佳命中分子为M1魚藤素小分子，对接分数达−11.0 kcal∙mol⁻¹，其次为M2槐黄烷酮G小分子，对接分数达−10.6 kcal∙mol⁻¹。结合分子动力学模拟，发现魚藤素和槐黄烷酮G小分子与受体蛋白具有强氢键作用和疏水相互作用，能形成稳定的复合物。结合自由能计算结果表明两分子与AChE蛋白结合具有类似的作用方式，有较高的AChE酶抑制活性，为AChE抑制剂开发的有效先导化合物。结论：运用该研究思路从天然产物数据库中挖掘出了对乙酰胆碱酯酶AChE有高抑制活性的小分子化合物，可为松材线虫AChE小分子抑制剂的开发提供物质参考。

Abstract: Objective: Similarity screening, molecular docking and molecular dynamics simulation were used to explore Acetylcholinesterase (AChE) inhibitors of Bursaphelenchus xylophilus from natural product databases. Methods: The protein structure of Bursaphelenchus xylophilus AChE was constructed by homology modeling technology, and rotenone with known inhibitory activity was used as the ligand of AChE to obtain the optimal docking parameters and mesh size. The AChE inhibitors were screened from natural product databases by multiple rounds of virtual screening strategies, such as structure-based similarity screening, drug-like evaluation, molecular docking, molecular dynamics simulation and binding free energy calculation. Result: A total of 21 hit molecules were obtained through multiple rounds of virtual screening, among which the top two best hit molecules were rotenin (M1) small molecule with docking fraction of −11.0 kcal∙mol⁻¹, followed by sophorflavanone G (M2) small molecule with docking fraction of −10.6 kcal∙mol⁻¹. Combined with molecular dynamics simulation, rotenin and sophorflavanone G small molecules showed strong hydrogen bond and hydrophobic interaction with target receptor protein, and could form stable complexes. Binding free energy calculation found that the two molecules combined with ACE protein had similar action mode and high inhibition activity on AChE enzyme, which were effective lead compounds for AChE inhibitor development. Conclusion: The small molecule compounds with high inhibitory activity on AChE were discovered from natural product database by using this research idea, which could provide material reference for the development of Bursaphelenchus xylophilus AChE small molecule inhibitors.