分子动力学模拟研究Fedratinib-JAK2/JAK3选择性
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摘要
通过动力学模拟获得JAK2高选择性抑制剂Fedratinib在JAK2和JAK3激酶中的结合构象,结合自由能的计算结果表明Fedratinib在JAK2中更稳定.将能量分解到结合位点氨基酸,分析发现当分子在JAK2中占据P-loop区的疏水口袋,并与附近Arg980和Asp994等氨基酸形成氢键时,可以增加相对于JAK2的选择性.
Molecular dynamic( MD) simulation was carried out in both JAK2-Fedratinib and JAK3-Fedratinib complex,respectively. Binding free energy was calculated in utilize the trajectory of MD. The results indicated the energy of JAK2-Fedratinib was lower than that of JAK3-Fedratinib,which demonstrate the different enzyme activity in two kinase. When binding free energy was decomposed into each residue of binding site,it could be found that when molecule occupies the pockets below P-loop and form H-bonds with residues nearby the selectivity for JAK2 over JAK3 may be highlighted. The results can provide insights for further development of more potent and selective JAK2 inhibitors.
Molecular dynamic( MD) simulation was carried out in both JAK2-Fedratinib and JAK3-Fedratinib complex,respectively. Binding free energy was calculated in utilize the trajectory of MD. The results indicated the energy of JAK2-Fedratinib was lower than that of JAK3-Fedratinib,which demonstrate the different enzyme activity in two kinase. When binding free energy was decomposed into each residue of binding site,it could be found that when molecule occupies the pockets below P-loop and form H-bonds with residues nearby the selectivity for JAK2 over JAK3 may be highlighted. The results can provide insights for further development of more potent and selective JAK2 inhibitors.
引文
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[2]Ivashkiv L.B.,Hu X.,Arthritis Rheum.,2003,48(8),2092—2096
[3]Yamaoka K.,Saharinen P.,Pesu M.,Holt V.E.Ⅲ,Silvennoinen O.,O’Shea J.J.,Genome Biol.,2004,5(12),253
[4]Pesu M.,Laurence A.,Kishore N.,Zwillich S.H.,Chan G.,O’Shea J.J.,Immunol.Rev.,2008,223,132—142
[5]Witthuhn B.A.,Quelle F.W.,Silvennoinen O.,Yi T.,Tang B.,Miura O.,Ihle J.N.,Cell,1993,74(2),227—236
[6]Firmbach-Kraft I.,Byers M.,Shows T.,Dalla-Favera R.,Krolewski J.J.,Oncogene,1990,5(9),1329—1336
[7]Harpur A.G.,Andres A.C.,Ziemiecki A.,Aston R.R.,Wilks A.F.,Oncogene,1992,7(7),1347—1353
[8]Rane S.G.,Reddy E.P.,Oncogene,1994,9(8),2415—2423
[9]Mercier E.,Lissalde-Lavigne G.R.,Gris J.C.,N.Engl.J.Med.,2007,357,1984—1985
[10]Tono C.,Xu G.,Toki T.,Takahashi Y.,Sasaki S.,Terui K.,Ito E.,Leukemia,2005,19,1843—1844
[11]Chen E.,Beer P.A.,Godfrey A.L.,Ortmann C.A.,Li J.,Costa-Pereira A.P.,Ingle C.E.,Dermitzakis E.T.,Campbell P.J.,Green A.R.,Cancer Cell,2010,18,524—535
[12]Bandaranayake R.M.,Ungureanu D.,Shan Y.,Shaw D.E.,Silvennoinen O.,Hubbard S.R.,Nat.Struct.Mol.Biol.,2012,19(8),754—759
[13]Clark J.D.,Flanagan M.E.,Telliez J.B.,J.Med.Chem.,2014,57(12),5023—5038
[14]Menet C.J.,Rompaey L.V.,Geney R.,Prog.Med.Chem.,2013,52,153—223
[15]Zhou T.,Georgeon S.,Moser R.,Moore D.J.,Caflisch A.,Hantschel O.,Leukemia,2014,28(2):404—407
[16]Kang C.M.,Zhao X.H.,Yu Y.Q.,LüY.T.,Chem.J.Chinese Universities,2016,35(3),550—554(康从民,赵绪浩,于玉琪,吕英涛.高等学校化学学报,2016,35(3),550—554)
[17]Wu Y.J.,Cui Y.L.,Zheng Q.C.,Zhang H.X.,Chem.J.Chinese Universities,2014,35(12),2605—2611(吴云剑,崔颖璐,郑清川,张红星.高等学校化学学报,2014,35(12),2605—2611)
[18]Li X.H.,Zhao J.W.,Teng H.,Chem.J.Chinese Universities,2010,31(2),374—378(李晓晖,赵俊伟,滕虎.高等学校化学学报,2010,31(2),374—378)
[19]Zhuang S.L.,Wang H.F.,Ding K.K.,Wang J.Y.,Pan L.M.,Lu Y.L.,Liu Q.J.,Zhang C.L.,Chemosphere,2016,144,1050—1059
[20]Muzzioli E.,Del Rio A.,Rastelli G.,Chem.Boil.Drug Des.,2011,78(2),252—259
[21]Berman H.M.,Battistuz T.,Bhat T.N.,Bluhm W.F.,Bourne P.E.,Burkhardt K.,Feng Z.,Gilliland G.L.,Iype L.,Jain S.,Fagan P.,Marvin J.,Padilla D.,Ravichandran V.,Schneider B.,Thanki N.,Weissig H.,Westbrook J.D.,Zardecki C.,Acta Crystallogr D,2002,58,899—907
[22]Maestro,Version 8.5,Schr9dinger,LLC.Cambridge,2008
[23]Friesner R.A.,Banks J.L.,Murphy R.B.,Halgren T.A.,Klicic J.J.,Mainz D.T.,Repasky M.P.,Knoll E.H.,Shelley M.,PerryJ.K.,Shaw D.E.,Francis P.,Shenkin P.S.,J.Med.Chem.,2004,47(7),1739—1749
[24]Halgren T.A.,Murphy R.B.,Friesner R.A.,Beard H.S.,Frye L.L.,Pollard W.T.,Banks J.L.,J.Med.Chem.,2004,47(7),1750—1759
[25]Case D.A.,Cheatham T.E.,Darden T.,Gohlke H.,Luo R.,Merz K.M.,Onufriev A.,Simmerling C.,Wang B.,Woods R.J.,J.Comput.Chem.,2005,26(16),1668—1688
[26]Frisch M.J.,Trucks G.W.,Schlegel H.B.,Scuseria G.E.,Robb M.A.,Cheeseman J.R.,Scalmani G.,Barone V.,Mennucci B.,Petersson G.A.,Nakatsuji H.,Caricato M.,Li X.,Hratchian H.P.,Izmaylov A.F.,Bloino J.,Zheng G.,Sonnenberg J.L.,Hada M.,Ehara M.,Toyota K.,Fukuda R.,Hasegawa J.,Ishida M.,Nakajima T.,Honda Y.,Kitao O.,Nakai H.,Vreven T.,Montgomery J.A.Jr.,Peralta J.E.,Ogliaro F.,Bearpark M.,Heyd J.J.,Brothers E.,Kudin K.N.,Staroverov V.N.,Kobayashi R.,Normand J.,Raghavachari K.,Rendell A.,Burant J.C.,Iyengar S.S.,Tomasi J.,Cossi M.,Rega N.,Millam N.J.,Klene M.,Knox J.E.,Cross J.B.,Bakken V.,Adamo C.,Jaramillo J.,Gomperts R.,Stratmann R.E.,Yazyev O.,Austin A.J.,Cammi R.,Pomelli C.,Ochterski J.W.,Martin R.L.,Morokuma K.,Zakrzewski V.G.,Voth G.A.,Salvador P.,Dannenberg J.J.,Dapprich S.,Daniels A.D.,Farkas.,Foresman J.B.,Ortiz J.V.,Cioslowski J.,Fox D.J.,Gaussian 09,Revision A.1,Gaussian Inc.,Wallingford CT,2009
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[29]Hou T.J.,Wang J.M.,Li Y.Y.,Wang W.,J.Chem.Inf.Model.,2011,51(1),69—82