The drug resistant mutations in human immunodeficiency virus type 1 (HIV-1) are a major impediment to successful highly active antiretroviral therapy (HAART) and new drug design. In order to understand the drug resistance mechanism of HIV-1 integrase (IN) mutually existed for multiple drug-resistant strains to the most potent IN inhibitors diketo acids (DKAs), three S-1360-resistant HIV-1 strains were selected and molecular docking and molecular dynamics (MD) simulations were performed to obtain the inhibitor binding modes. Based on the binding modes, compelling differences between the wild-type and the 3 mutants for IN have been observed. The results showed that: 1) In the mutants, the inhibitor is close to the functional loop 3 region but far away from the DNA binding site. Different binding sites lead to the decrease in susceptibility to S-1360 in mutants compared to the wild-type IN. 2) The fluctuations in the region of residues 138~166 are important to the biological function of IN. 2 hydrogen-bonds between S-1360 with residues N155 and K159 restrict the flexibility of the region. Drug resistant mutations result in a lack of the interaction, consequently, the less susceptible to S-1360. 3) In the 3 mutant IN complexes, the benzyl ring of S-1360 is far from the viral DNA binding site, thus, S-1360 can not prevent the end of the viral DNA from exposure to human DNA. 4) After T66I mutation, the long side chain of I occupied the active pocket in the 3 mutants，consequently， the inhibitor could not move into the same binding site or have the same orientation. All the above contribute to drug resistance. These results will be useful for the rational inhibitor modify and design.