An　approved　peptidic　HIV-1　fusion　inhibitor,　T-20,　has　shown　significant　promises　in　clinical　applications.　However,　T-20　must　be　injected　twice　daily　and　is　too　expensive.　Consequently,　it　is　necessary　to　research　oral　small　molecule　HIV-1　fusion　inhibitors.　In　an　effort　to　understand　the　molecular　mechanism　of　the　small　molecule　inhibitors　binding　to　gp41,　we　have　carried　out　docking　studies,　explicit　solvent　molecular　dynamics　simulations,　and　binding　free　energy　calculations.　The　results　of　calculated　binding　free　energy　are　in　agreement　with　the　experimental　data.　Further　analysis　of　the　binding　free　energy　components　reveals　the　dominant　contributions　to　hydrophobic　interactions.　These　results　could　be　used　to　design　more　effective　HIV-1　inhibitors　targeted　to　the　hydrophobic　pocket　of　HIV-1　gp41.　(c)　2006　Elsevier　B.V.　All　rights　reserved.