The　c-Jun　N-terminalkinase　(JNK)　is　involved　in　a　variety　of　important　cellular　processes　and　aberrant　JNK　activity　isassociated　with　many　human　diseases.　The　ligandbasedand　receptorbasedalignment　rules　were　used　to　build　3D-QSARmodelsfor　a　series　of　N-benzylisatin　oximes　JNK　inhibitors.　The　best　models　were　obtained　for　the　receptorbasedalignment　with　Co　MSIA　combining　steric　(S),　electrostatic　(E),　and　hydrogen　bond　donor　(D)　and　hydrogen　bond　acceptor　(A)　fields　(q　2　=　0.759,r　2　=　0.966,　r　2pred　=　0.703).　Based　on　the　contour　maps　of　RB　Co　MSIA　model,　some　key　structural　factors　responsible　for　inhibitoryactivity　were　investigated.　Large　groups　at　Nsubstituentor　R6　position　are　preferred　to　interact　with　hydrophobic　residues　Ile70,Asp150,　Ala151,　Asn152　and　Ser193.　Electrondonatingor　hydrogen　bond　donor　groups　on　the　isatin　ring　would　form　polar　andhydrogen　bond　with　the　negativechargedresidue　Glu147.　In　addition,　electronwithdrawinggroups　or　hydrogen　bond　acceptorgroup　near　the　Nsubstituentwould　enhance　inhibitory　activity.　The　results　are　in　good　accordance　and　complementary　to　eachother.　The　developed　models　could　provide　guidance　in　the　rational　design　of　more　potent　and　selective　JNK　inhibitors.　©　2013　Journal　of　Chinese　Pharmaceutical　Sciences,　School　of　Pharmaceutical　Sciences,　Peking　University.