Human　immunodeficiency　virus　type　I　integrase　(IN)　is　an　essential　enzyme　in　the　life　cycle　of　this　virus　and　also　an　important　target　for　the　study　of　anti-HIV　drugs.　In　this　work,　the　binding　modes　of　the　wild　type　IN　core　domain　and　the　two　mutants,　that　is,　W132G　and　C130S,　with　the　4-hydroxycoumarin　compound　NSC158393　were　evaluated　by　using　the　＂relaxed　complex＂　molecular　docking　approach　combined　with　molecular　dynamics　(MD)　simulations.　Based　on　the　monomer　MD　simulations,　both　of　the　two　substitutions　affect　not　only　the　stability　of　the　128-136　peptides,　but　also　the　flexibility　of　the　functional　140s　loop.　In　principle,　NSC158393　binds　the　128-136　peptides　of　IN;　however,　the　specific　binding　modes　for　the　three　systems　are　various.　According　to　the　binding　mode　of　NSC158393　with　WT,　NSC158393　can　effectively　interfere　with　the　stability　of　the　IN　dimer　by　causing　a　steric　hindrance　around　the　monomer　interface.　Additionally,　through　the　comparative　analysis　of　the　MD　trajectories　of　the　wild　type　IN　and　the　IN-NSC158393　complex,　we　found　that　NSC15893　may　also　exert　its　inhibitory　function　by　diminishing　the　mobility　of　the　function　loop　of　IN.　Three　key　binding　residues,　that　is,　W131,　K136,　and　G134,　were　discovered　by　energy　decomposition　calculated　with　the　Molecular　Mechanics　Generalized　Born　Surface　Area　method.　Characterized　by　the　largest　binding　affinity　W131　is　likely　to　be　indispensable　for　the　ligand　binding.　All　the　above　results　are　consistent　with　experiment　data,　providing　us　some　helpful　information　for　understanding　the　mechanism　of　the　coumarin-based　inhibitors.　(C)　2009　Wiley　Periodicals,　Inc.　Biopolymers　91:　700-709,　2009.