A targeted virtual screen to the N-helix hydrophobic pocket on HIVgp41 was performed using DOCK followed by re-ranking with a new footprint-based scoring function which employed native gp41 C-helix residues as a reference. Of ca. 500,000 small molecules screened, 115 were purchased, and 7 hits were identified with favorable binding (K i ), cell–cell fusion (IC 50 ), and cytotoxicity (CC 50 ) profiles. Three of the seven active compounds would not have been discovered without the use of the footprints, demonstrating the utility of the method for structure-based design when a known reference compound or substrate is available.