At　present,　the　approved　HIV　integrase　(IN)　inhibitors　are　all　diketo-acids　(DKAs).　To　have　a　better　understanding　of　DKA　inhibitors,　comparative　molecular　field　analysis　(CoMFA),　comparative　molecular　similarity　indices　analysis　(CoMSIA),　docking,　and　molecular　dynamics　(MD)　were　performed　on　88　DKAs.　The　constructed　CoMFA　and　CoMSIA　models　were　shown　to　be　statistically　significant　for　the　training　set　with　the　cross-validated　value　(q(2))　of　0.94,　non　cross-validated　value　(r(2))　of　0.96　for　CoMFA;　q2　of　0.96,　r(2)　of　0.94　for　CoMSIA.　External　q(2)　of　the　test　set　Q(F1)(2),　Q(F2)(2)　and　Q(F3)(2)　were　0.79,　0.77　and　0.81　for　CoMFA;　Q(F1)(2),　Q(F2)(2)　and　Q(F3)(2)　were　0.60,　0.56　and　0.63　for　CoMSIA.　Further　interpretation　of　contour　maps　provided　instructive　insights　into　the　optimization　and　designing　of　lead　compounds.　The　interaction　between　IN　and　two　DKAs　(the　inhibitors　with　the　highest　and　lowest　activity)　were　investigated　using　＇relaxed　receptor＇　molecular　docking　and　molecular　dynamics　simulations.　Molecular　mechanics　Poisson-Boltzmann　surface　area　(MM-PBSA)　and　molecular　mechanics　Generalized-Born　surface　area　(MM-GBSA)　were　employed　to　evaluate　the　binding　affinity　and　the　energy　decomposition　for　residues,　respectively.　Further　analysis　indicated　that　the　dominating　effect　of　van　der　Waals　drives　the　binding　of　IN　and　DKA　inhibitors　and　key　residues.　In　addition,　we　found　that　the　MD　conclusion　was　consistent　with　QSAR　models　after　the　analysis　of　the　interaction　between　DKAs　and　each　residue.　These　findings　may　be　of　immense　importance　in　the　development　of　DKA　inhibitors.