抗肿瘤化合物WX-132-18B与微管蛋白的分子对接研究

Anti-cancer agent WX-132-18B with tubulin:a molecular docking study

目的利用计算机辅助分子对接技术预测WX-132-18B与微管蛋白的合理结合方式,为其结构衍生化和设计新化合物提供理论支持。方法通过软件DS3.0将微管蛋白与化合物2和3的复合晶体结构5OSK和6BR1相重叠,并将5OSK中的水分子W615嵌入到6BR1中形成新的蛋白结构6BR1′,然后利用DS3.0中的分子对接模块CDOCKER将6BR1′和WX-132-18B进行对接。结果WX-132-18B的最优构象与微管蛋白的结合能为-29.31 kcal/mol。其中,7-甲氧基-3,4-二氢喹吓恶啉-2(1H)-酮环中胺基上的氢原子作为氢键给体与水分子W615中的氧原子形成氢键,2-甲基喹唑啉环中1位的氮原子与水分子W675近端的氢原子形成氢键;同时,2-甲基喹唑啉环中的苯环与Alaβ314结构中的甲基形成σ-π相互作用。水分子W615和W675分别与氨基酸Asnα101、Thrα179和Valβ236、Cysβ239形成氢键,起到氢键传递的作用。结论WX-132-18B通过水分子在微管蛋白α、β亚基之间与关键氨基酸形成相互作用。2-甲基喹唑啉啉环处于经典微管蛋白聚集抑制剂中3,4,5-三甲氧基苯基(A环)的结合位置;7-甲氧基-3,4-二氢喹吓恶啉-2(1H)-酮环中的甲氧基苯基处于经典微管蛋白聚集抑制剂中甲氧基芳基(B环)的位置,其中的哌嗪-2-酮环除起到构象限制的作用外,还增加了与微管蛋白α亚基的相互作用。

Objective To explore the reasonable combination of WX-132-18B with tubulin by computer-aided molecular docking technology,so as to provide theoretical support for its structural derivatization and design of new compounds.Methods The tubulin and compound 2 or 3 co-crystallized structures 5OSK and 6BR1 were first overlapped with software DS3.0,and the water molecule W615 in 5OSK was embedded into 6BR1 to form a new protein structure 6BR1′.Then WX-132-18B was docked into 6BR1′by the CDOCKER module of DS3.0.Results The binding energy of the optimal conformation of WX-132-18B with protein was-29.31 kcal/mol.Hydrogen bonds were formed between the hydrogen atom of the amine group in the 7-methoxy-3,4-dihydroquinoxaline-2(1H)-one ring and water molecule W615,and also formed between the 1 position nitrogen atom in the 2-methyl quinazoline ring with the water molecule W675.Aσ-πinteraction was formed between the benzene ring of the 2-methylquinazoline ring and Alaβ314.In addition,the water molecules W615 and W675 formed hydrogen bonds with the amino acids Asnα101 and Thrα179,and the amino acids Valβ236 and Cysβ239,respectively,playing the role of hydrogen bond transfersome.Conclusion The key interactions were formed between WX-132-18B and amino acids in the middle of tubulinαandβsubunits via water molecules.The 2-methylquinoline ring and the methoxyphenyl group of the 7-methoxy-3,4-dihydroquinoxaline-2(1H)ring were binding at the sites of 3,4,5-trimethoxyphenyl group(A ring)and the methoxyaryl group(B ring)of the classical tubulin polym?erization inhibitors,respectively.The piperazin-2-one ring provides additional interaction with tubulin in addition to its conformational restriction function.