β微管蛋白中紫杉醇(Taxol)结合腔的性质分析

Property Analysis of Taxol-binding Site in β-Tubulin

采用多拷贝同时搜寻法(MCSS),并结合现有微管抑制剂的SAR及3D-QSAR对β微管蛋白中Taxol(紫杉醇)结合腔的性质进行了分析.结构研究结果表明,Taxol结合腔以疏水性质为主,并指出官能团分布的具体位置:在Phe270上方(Leu361-Pro272-Leu273-Leu228之间)的弧形区域、Asp26羧基下方及其与G lu22羧基之间、M-loop的中部,以及Asp224内侧且靠近Arg276的胍基的位置.而Asp224的内侧又是新提出的结合位点.研究结果符合现有微管抑制剂的SAR,为现有抗肿瘤药物的结构改造以及小分子微管抑制剂设计提供了理论依据.

Multi-copy simultaneous search （MCSS） was used to analyze the maps of four kinds functional groups （the hydrophobic, hydrophilic, positive charge and negative charge functionalities） in the taxol-binding site of theβ-tubulin. Based on the result, the hydrophobic groups were distributed above Phe270, and then among Asp26, Glu27, Val23 and Pro358. While the hydrophilic functionalities scattered around the hydroxyl of Glu22, Asp224 and Asp26 and beneath the guanidyls of Arg276 and Arg282. The positive charge functionalities were around the carboxyl of Asp224, Asp26 and Glu22, and the hydroxyl of Gln278. The negative charge ones were beneath the guanidyl of Arg276 and Arg282, and between the sidechains of His22 and Leu228