This　discovered　and　optimized　several　novel　HIV-1　fusion　inhibitors　and　further　evaluated　the　inhibitory　activities　of　these　compounds　in　vitro.　Here,　we　have　reported　the　computer-aided　design,　synthesis,　and　biological　evaluation　of　a　series　of　small　molecule　fusion　inhibitors　targeting　HIV-1　gp41.　Based　on　the　structure　of　inhibitor　(NB2),　we　carried　out　de　novo　design　and　screened　out　a　series　of　novel　structure　molecules　by　using　Leapfrog　and　Autodock　programs.　Our　structure-based　modification　obtained　a　potent　fusion　inhibitor　(IC(50)　=　41.1　mu　g/mL).　Several　novel　compounds　were　discovered　as　fusion　inhibitors,　which　suggested　that　our　design　methodology　is　reliable,　paving　the　way　for　de　novo　design　of　novel　small-molecule　HIV　inhibitors　targeting　gp41.