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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 investigate the molecular resistance mechanism of integrase. Methods The molecular docking program of Discovery Studio 2.5 software was used to construct a complex model of integrative enzyme Raltegravir (RAL) with integrase core region protein crystal structure (1BL3). Combined with the known integrase resistance A series of integrase protein resistance gene mutants were constructed by mutating Q148H, N155H, Y143C and other wild-type residues (T97A, A128T, E138K, E157Q and G163R). In order to further calculate the HIV-1 integrase protein amino acid residues mutation, and the difference between the free molecular energy and retegrate and retegrate and different integrase protein resistance gene Free energy of binding between mutants. The main result of the mutation Q148H, N155H, Y143C and RAL are located in the active site of the integrase, can significantly alter the binding between the core region raltegravir free energy of the crystal, the most obvious change to N155H, followed Q148H, Y143C. In addition, mutations in the wild-type gene also caused a certain degree of freedom to change, with some resistance significance. Conclusion It is confirmed that the mutation at the drug resistance site leads to an increase in the binding free energy between the integrase protein and reteglutide, which affects the binding between the drug and the integrase.