Molecular　docking,　molecular　dynamics　(MD)　simulation　and　molecular　mechanics　Poisson-Boltzmann　surface　area　(MM-PBSA)/molecular　mechanics　Generalized　Born　surface　area　(MM-GBSA)　analysis　are　applied　to　predict　the　binding　mode　of　two　N-substituted　pyrrole　derivate　inhibitors　to　the　hydrophobic　pocket　in　HIV-1　envelope　protein　gp41.　Taking　into　account　the　flexibility　of　the　receptor,　multiple　receptor　conformations　are　used　in　docking　with　the　ligands,　which　results　in　several　possible　binding　modes.　MD　simulations　and　MM-PBSA　binding　energy　calculations　are　performed　on　all　the　binding　modes　to　identify　the　most　favorable　binding　estimate.　The　MM-PBSA　results　indicate　that　the　binding　is　mainly　driven　by　non-polar　interactions,　while　polar　interactions　determine　the　orientation　of　the　ligands　binding　into　the　target　site.　Further　analysis　reveals　the　key　residues　and　ligand-receptor　interactions　which　contribute　significantly　to　the　binding　affinity.　This　study　provides　useful　information　for　rational　design　and　optimization　of　N-substituted　pyrrole　derivatives　as　HIV-1　fusion　inhibitors.