The　drug　resistant　mutations　in　human　immunodeficiency　virus　type　I　(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　similar　to　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.