用分子对接技术预测HIV-1整合酶抑制剂药物雷特格韦的耐药机制

Exploring drug resistance mechanism of HIV-1 integrase inhibitor raltegravir by molecular docking

目的探究整合酶的分子耐药机制。方法研究采用Discovery Studio 2.5软件模块的分子对接程序,构建整合酶药物雷特格韦(Raltegravir,RAL)与整合酶核心区蛋白晶体结构(1BL3)的复合物模型,并结合已知的整合酶耐药突变位点Q148H、N155H、Y143C和其他野生型残基突变(T97A、A128T、E138K、E157Q、G163R),构建一系列整合酶蛋白耐药基因突变体。以此进一步计算艾滋病病毒Ⅰ型(HIV-1)整合酶蛋白发生氨基酸残基突变后,与雷特格韦之间分子自由能的改变,并分析雷特格韦与不同整合酶蛋白耐药基因突变体之间的结合自由能。结果主要突变Q148H、N155H、Y143C均位于RAL与整合酶的活性中心,均可明显改变雷特格韦与核心区晶体之间的结合自由能,以N155H改变最为明显,其次为Q148H、Y143C。此外,野生型基因突变也造成一定程度的自由能改变,具有一定的耐药性意义。结论证实耐药位点突变导致整合酶蛋白与雷特格韦之间结合自由能增大,影响药物与整合酶的结合。

Objective To explore drug resistance mechanism of HIV-1 integrase inhibitor raltegravir. Methods The molecular docking simulations （Discovery Studio 2.5 software） was used to construct the complex model of in- tegrase drug （raltegravir, RAL） and integrase structure （1BL3）, and construct a serial of drug-resistant mutant of 1BL3 in combination of some known resistance mutations （Q148H, N155H, and Y143C）, and other wild type gene mutations （T97A, A128T, E138K.E157Q, and G163R）. Free energy changes of molecules of RAL and 1BL3 with mutations of the amino acid residues were calculated, and binding energy between RAL and 1BL3 were furtherly an- alyzed. Results The docking results showed that Q148H, N155H, and Y143C were located within integrase active pocket of RAL and 1BL3, and the mutations can significantly increase the binding free energy between RAL and ]BL3. NZ155H mutation had the most obvious effect on the energy change, followed by Q148H and Y143C. In addi- tion, wild gene mutations also changed binding free energy to a certain degree, which showed some sort of drug re- sistance. Conclusion This study showed resistance mutations led to increases of binding free energy between RAL and 1BL3, affecting the combination between RAL and HIV-1 integrase.