To　have　a　better　understanding　of　the　relationship　between　structures　and　inhibitory　activities　of　HIV　fusion　inhibitors,　topomer　comparative　molecular　field　analysis　(Topomer　CoMFA)　and　hologram　quantitative　structure-activity　relationship　(HQSAR)　were　applied　to　study　a　series　of　pyrrole　derivatives　as　potential　HIV　fusion　inhibitors.　Statistical　results　from　the　Topomer　CoMFA　model　showed　believable　predictability　based　on　the　non-cross-validated　value　(r　(2)　=　0.96),　and　the　cross-validated　value　(q　(2)　=　0.63).　The　r　(2)　and　q　(2)　from　the　HQSAR　model　were　0.96　and　0.66,　respectively,　which　also　indicated　the　excellent　predictability.　External　validations　further　proved　the　predictive　potent　of　these　two　models　with　the　values　of　0.96　for　both　the　two　models.　Statistical　results　of　the　two　models　showed　that　they　are　all　credible.　In　addition,　we　found　a　phenomenon　that　for　some　compound,　bulky　and　negatively　charged　substitutions　were　favourable　to　its　activity　in　the　Topomer　COMFA,　but　nitrogen　contributed　more　positively　than　the　bulkier　and　more　negative　chorine　in　the　HQSAR.　Therefore,　in　order　to　obtain　more　potential　hits,　the　two　models　should　be　combined　together.　These　studies　would　provide　insights　for　the　structure-activity　relationship　understanding　of　the　small-molecule　fusion　inhibitors　and　be　helpful　for　the　rational　design　of　novel　fusion　inhibitors　in　the　future.　Graphical　Abstract　Steric　and　electrostatics　contour　maps　of　compound　A1　were　analysed　to　have　a　further　study　on　structure　necessities　of　pyrrole　derivatives　as　HIV-1　fusion　inhibitor.　[GRAPHICS]　.