A　three-dimensional　pharmacophore　model　was　developed　for　a　considerable　number　of　pyrrolidine-based　and　butane-based　chemokine　(C-C　motif)　receptor　5　(CCR5)　antagonists,　which　can　block　the　entry　of　human　immunodeficiency　virus　type　1　(HIV-1)　by　inhibiting　the　interaction　of　HIV-1　envelope　protein　and　CCR5.　The　pharmacophore　model　was　generated　using　a　training　set　consisting　of　25　carefully　selected　antagonists　with　the　diverse　molecular　architecture　and　bioactivity,　as　required　by　the　Catalyst/HypoGen　program.　The　activity　of　the　training　set　molecules　expressed　in　IC50　(half-inhibitory　concentration)　covered　from　0.06　to　10000　nmol·L-1.　The　most　predictive　pharmacophore　model　(Hypo　1),　consisting　of　two　positive　ionizable　points　and　three　hydrophobic　groups,　had　a　correlation　of　0.924　and　a　root　mean　square　of　1.068,　and　a　cost　difference　of　63.67　bits　between　the　null　cost　and　the　total　cost.　The　model　was　applied　in　predicting　the　activity　of　74　compounds　as　a　test　set.　The　results　indicated　that　the　model　was　able　to　provide　clear　guidelines　and　accurate　activity　prediction　for　novel　antagonist　design.　©　2007　Chinese　Chemical　Society　and　College　of　Chemistry　and　Molecular　Engineering,　Peking　University.