In　this　study,　a　series　of　1,3,4-trisubstituted　pyrrolidine-based　CCR5　receptor　inhibitors　were　taken　as　our　target　with　the　method　of　the　three-dimensional　quantitative　structure-activity　relationship　(3D-QSAR)　analyses　in　order　to　investigate　the　interactions　between　CCR5　receptor　and　their　inhibitors.　For　a　comparison,　Comparative　Molecular　Field　Analysis　(CoMFA)　and　Comparative　Molecular　Similarity　Indices　Analysis　(CoMSIA)　were,　respectively,　used　to　build　predictive　models,　which　were　generated　from　a　training　set　consisting　of　72　selected　molecules,　derived　from　literatures.　Two　alignment　rules,　including　rigid　body　rms　(root　mean　square)　fit　and　field　fit,　were　performed　in　the　superimposition　of　inhibitors　structures.　As　a　result,　a　better　CoMFA　model　based　on　common　structure　alignment　obtains　a　conventional　correlation　coefficient　r(2)　of　0.952　and　a　leave-one-out　cross-validated　coefficient　q(2)　of　0.637,　while　the　desirable　CoMSIA　model　based　on　the　same　alignment　rule　acquires　the　r(2)　of　0.958　and　the　q(2)　of　0.677.　To　further　validate　the　reliability　of　the　models,　we　also　investigated　into　the　externally　test　set　composed　of　39　molecules　under　the　criterions　of　squared　correlation　coefficient　between　experimental　and　predicted　activities　with　intercept　R-2　and　without　intercept　R-0(2),　along　with　R-m(2)　as　the　modified　R-2　with　a　penalty　function　due　to　difference　between　R-2　and　R-0(2).　At　last,　the　contour　map　also　provides　a　visual　representation　of　contributions　of　steric,　electrostatic,　hydrogen　bond　and　hydrophobic　fields,　as　well　as　the　prospective　binding　modes.　These　results　may　provide　meaningful　guidance　to　the　further　work　including　the　similar　lead　compounds＇　structure　modification　and　activity　prediction.　(C)　2008　Published　by　Elsevier　Masson　SAS.