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Study on the drug resistance and the binding mode of HIV-1 integrase with LCA inhibitor

查看全文 作　　者：HU JianPing1,2, CHANG Shan1, CHEN WeiZu1 & WANG CunXin1 1 College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100022, China;2 Department of Chemistry & Life Sciences, Leshan Normal University, Leshan 614004, China 高影响力作者 出　　处：《Science China Chemistry》索引2007年第50卷第5期,共10页高影响力期刊 基　　金：Supported by the National Natural Science Foundation of China (Grant Nos. 30500429 and 30670497) ;Beijing Natural Science Foundation (Grant No. S072002) 摘　　要：Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding mode of the wild type IN core domain and its G140S mutant with L-Chicoric acid (LCA) inhibitor were investigated by using multiple conformation molecular docking and molecular dynamics (MD) simulation. Based on the binding modes, the drug resistance mechanism was explored for the G140S mutant of IN with LCA. The results indicate that the binding site of the G140S mutant of IN core domain with LCA is different from that of the core domain of the wild type IN, which leads to the partial loss of inhibition potency of LCA. The flexibility of the IN functional loop region and the interactions between Mg2+ ion and the three key residues (i.e., D64, D116, E152) stimulate the biological operation of IN. The drug resistance also lies in several other important effects, such as the repulsion between LCA and E152 in the G140S mutant core domain, the weakening of K159 binding with LCA and Y143 pointing to the pocket of the G140S mutant. All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing the drug of anti-HIV based on the structure of IN. 关 键 词：molecular docking, MD simulation, HIV-1 IN, DRUG design
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