ʥЩ˕Ȍ̪єпÉwgm <16 October, 2014> SAR News No.27 ̨ʮ SAR News ψͦb]3,. ҠҠҠ 2 ʃѓ þЂ ҠҠҠ 3 ̿˫ ο ҠҠҠ 10 ƍ̋ Ąϕ ҠҠҠ 18 ҇ʁ б ҠҠҠ 25 ҇ʫ ̌ѥ ///// Perspective/Retrospective ///// ̶̄3JSeağπ5ńIͭA kinase јƩěϢϟNÙ3 ///// Cutting Edge ///// Seağπ3J FMO ˏ0ŗМź̧ȧφ5Ыʳ YN̊(ɜϕQu`ŅƫÓȳȪπ5ğώ ///// Activities ///// ҜżŖҝ ʥЩ˕ȌW 2014 ђôżŖ ũѨĭ#JıπŜђ̟5̂˻0Ʒʉ ҜÉŖҝ ͒ 42 ŦʥЩ˕Ȍ̪єefT ҠҠҠ 27 SAR News No.27 (Oct. 2014) SAR News ψ ͦ b ] 3 , . ƺ!õ(ҐťϚdzґ6ʥЩ˕Ȍ̪є5¢̑NҐHansch-Fujita ˏN6"C|mϪϷEщ ƚĭƞϟ͘21ґ̕2Jϖ˲ҐϚǩґH̯CJ05ƋđNψ̂!.J 5þ0ў61 O2ȤˏD,/#=.N˵H!ď#06ũѨ/IȄ$þ0ў5G3&K3G+.˵H !ďKJпĐ0&K)/6ϔ2пĐJ0Nψ!.J ĉ5ɗƛ6ʥЩ˕Ȍ̪є ̶͋ÉҐDzпÉ5ĚБґ5αϭŒҐStructure Activity Relationships Society of JapanґNeSh!(D 5/Iʂ̳5ʥЩ˕Ȍ̪є5¢̑̕2JΫ5þ/˵H!)KJ0N̹!.J @(ƺ!õ (ťϚdz50&KNɝ/ˀǞ3ʩđJmStɗƛ5сΆ6QPpt5ҞNSf !.J ҐsdSқ҇ʫ̌ѥґ SAR News 6ʥЩ˕Ȍ̪є̶͋3є#JȒż̟ãṆ̨0!2001 ǟ 10 ɺ3DzпÉ5ĚБ/JʥЩ˕ Ȍ̪є̶͋É3GI̟υђƖK@!( ψͦ5b]3,.6пÉͅυǻDğĒDzĔ5D5N Ø̊!.@!(ʃŌGIΗɲsdS6&5@@ʬєŒпĐ5ANпÉʱǬŒ̈́Ґαϭґ3ɌϞ !.ǭͳĖ̊#J002I@!( ҐͺѦƗŞÉґ -2- SAR News No.27 (Oct. 2014) ///// Perspective/Retrospective ///// ̶̄3JSeağπ5ńIͭA kinase ј Ʃ ě Ϣ ϟ N Ù 3 ̄ĭƞ̶͋ȣ ScSVgȧφź̶̧͋im ʃѓ þЂ 1. はじめに Ƞǻ5҇ǩͮ˟Ȟя0ВNő"!. 1970 ǟH 1990 ǟÁĔѵ3.ɡʃ5ώπÇʡ3 Jğπ6ҍъʀNР( @(&K0ƺ!ЭKJdz/ɡʃ5ScSVgĐш5ź ̸̶͋ȩЄDƦNͯ9Nature, Science, Cell 215˖ϩ5ϲɗȿЗɔ6ʯ͜ýЫŭ0ʽ=. гΫ52@/œ!.J !!&5ź̸̶͋5Ȟʎ6Ȅ$!Dɡʃŭĉ5ıπŜ ђ̟3ͯ9,.6H$1990 ǟÁÂњɜπ5ȦϪɔˡƺõœ3J ˺3New England Journal of Medicine E Lancet 215ıƞƵѐϩ5ɡʃH5ϲɗȿЗɔ6ʯ͜ýЫŭGIDκ !ƺ2ɹС/6¥ŭ215ɜΧŭNŦJ˻ˍͳ.J ͜ŭ3.6ź̸̶ ͋NıπŜ3ͯ9,JQYsQ̟5{SXoʮ0ϫ̈!˕̟2ğπ˕ħ΅ IǤHKȞʎNȶ.J[1] ɝɡʃ/6îĂ2ğπ{SXoҐ˺3Σǥʹ Ѡ@(6uĭŏ˹@/ЫCJ0ňΚ2|SSoґΕ+.H$QY sQ5ğπehŭĉ/ıπŜ3ͯ9,27Iʯ͜5ZP3ȴ+. KJ±ÙDϔHKJ 5G2ŭĉ5ź̸̶͋0ıπŜђ̟5ѓ5\pNŵCJ(C3̄ĭƞ̶͋ȣҐ̶̄ґ /62010 ǟ3ɢρˉπŜǐʡG9Qgrgώπ3.m]g5ђ̟N§Ƹ! (ǻρá̏ʾNРğπı̝ȧφź̧^Ngmt%( ʃ͉/6̶̄3 J&KH5^NЧ!(ğπ˕ħ5̂˻0ýυ!.JÙ0!.̡τ̚ˋ̝πN̨ȵ !( kinase јƩěϢϟ5Ù3,.ͫ½#J 2. 理研 創薬・医療技術基盤プログラム ğπı̝ȧφź̧^ҐDMPґ6ɡʃ̟5ѯɜ̣2ıπEı̝ȧφ5ğďN̨ʧ 3!.̶̄5ScSVg̶͋/ŹMK(̶͋ź̧N˕̊!̶̄5Ŏ̶͋imEƋ ƞ͕/ϔďK(ehNńIıπŜı̝ȧφ3ͯ9,J0Npe0!. J ̚ќND(2̶̄6ΣǥϦ҃NƦɞ#J§Ó362K20HDMP ȾЫ#Jr fU]t6жđ2mS^/ΣǥϦ҃Âњ5ђ̟NȯoÇʡώπÇ ʡJ6ı̝ʬє<Ƹď#JȄϒIū 1 3̹# 3 ͇Ѻ5ďņȠ̓NϢƤ!.J ū 1. ̶ ͋ ђ ̟ g r f 0 ď ņ Ƞ ̓ -3- SAR News No.27 (Oct. 2014) Exit 1 6̈˹ƞ̶͋Ώ3GJğπʧ̣̟ϔʹѠ/5Ƹď/J Exit 1 6Ǽʉ5QYs Qğπ3.DϦAHK.(ȧφ̣3Ѩɩǩ5҇ğπʧ̣ͪΘı̝ȧφ/+(I _ptƹĐш5ŽŏDƉgh3Ņˢ!/2ŽŏƉ+( &/ DMP /6uĭŏ˹ȪÓʹѠ/5ƸďҐExit 2ґ0ΣǥϦ҃5ʹѠ/5ƸďҐExit 3ґN ϢƤ!&KH5grf@/ DMP ï/ğπǁђ/JȗĪNɕó!,,J ̶̄6ɹý͐5ğπєЪź̧ȧφNȴ,Ϗɔ5̶͋imNɻ#J Ŏ̶͋imH ğπ5̂Ž/Ʀ̣̊3Ʀɞ/JȧφNзƤ!8 ,5ğπź̧wptNͺȞ!(Ґū 2ґ ğ πź̧wpt5{6ŎrnҐTMLґ fU]tnҐPLґ5D0/ rfU]tNȾЫ#J ŧA3̶̄ĉ32ȧφź̧3,.6ƈпʬє05ЪɈE QTtke^3G+.Y{!.J ʊ¹ƋƞҐʊƋґğπXSyei mẺʡȧφͷŏ̶͋ȣҐ̉ͷ̶ґ06ĭŏ˹S5ɂÛg]w^͕5Ѯ/ ƭȽ3ЪɈ!.J @(ΣǥȈ̊3,.6Ƌƞ5ıƞпEı̝ʬє05ЪɈNЫC.J Ŏğπig0ğπı̝ȧφź̧06Â5єß3J euĭŏ˹Nϔ)#i g/6_Y{]ź̧euĭŏ˹ȼͨź̧ҐHTSґğπĐƚϢϟź̧m|]Ї ϛʌҐX NMR̈ĭƞϥÝґź̧NϢΆ!.J uğďigG9uĭŏ ˹ɹжĭig/6m|]Їϛʌź̧ğπĭƞź̧ğπSf^ź̧NϢΆ!. J ȪÓıπ/6ȪÓź̧ȪĽm|]ЇϱώʬΚNȴ,m|]Їϛʌź̧0ЪɈ!.̶ ͋NЫC.J[2] ý͐ϟ̓͘ƞź̧/6ɔǟǻ5Ʀ̊ĭN̨ȵ!(ʮ¢Á5ȧφђ̟Nυ +.ID. E. Shaw Research ђ̟!( Anton 3įɖ#JĐƚħĠƞƵ̊ϟ͘ʬҐMD-GRAPE4ґ 5Ʀ̊ĭNЫC.J ğπź̧Nɻ#JŎ̶͋im6ğπÂƈ5Ŭɻ5peDȴ,5/̶͋im0 DMP 0Nʩ5єß0#Jtp]gxftÓĘ5̷͏чϒ/J 5G2 xft6ώπÇʡ/6Ω̣/JQYsQ̶͋ʬє/6́! @(DMP 6ǻρ^sR]m53tWXxfҐrfU]t5Ȼ ū 2. DMP 5 t p ] g x f t -4- SAR News No.27 (Oct. 2014) ȬEȾЫN§Ƹ#JґȧφͱȲxfҐȧφź̧5DZĭNȵƸ#JґfU]t nҐugrfÂњ5fU]tNͱȲ#Jґ±ʡђ̟ƧҐÇʡ05·ˠNȯDz#Jґ ϕĘ̓ƞxfҐıπŜȦϪ3œ(ɝыNȵƸ#JґΣǥђ̟xfҐΣǥ ђ̟5ЫCɝNȵƸ#JґNϢ.JǹH5>0O16ώπÇʡ3.ΣǥèύŜN ğď!(ͮ҃5J»ʅ/Iğπ5Ȅϒ ňʭ2ŎʹѠŎѴŷ3ͮ҃5J»ʅN@ /сΆ!.J0DDMP 5Ƌ2˺ȁ/J 2.1 創 薬 テ ー マ ・ プ ロ ジ ェ ク ト の 採 択 と 推 進 rfU]t6g]w^ʹѠ(S0, S1, S2, S3)uʹѠ(L1, L2, L3)Σǥ ʹѠ(P0, P1, P2, P3)5 3 Yrb11 ʹѠ3ĐKS0 HɹͬıπŜҐ@(6ı̝ȧφґN ĬŔ!J˺ϣNńǽ#J L2 @/5grfNrђ̟èύŜNзȬ!( L3 grf ÂњNfU]t0řO/J rfU]t5ĩѦ6̶̄ĉ̶͋imEƋƞ215̶͋ʬєHȾξNŅJ ɝˏ0 f/ĄĩNυɝˏ0J Ąĩ5Žŏ5ȈĩЄʙ6̶̶̄͋Ώ3ћƤ K.JҐąő̶͋Ώ5 1 »3̶̶̄͋Ώā+.K7ň ̶̶̄͋Ώϔ,H2Žŏ 36ǻУ5ğπɋɆxpt]5ğπv~H̎!ОB0/Jґ ȈĩK(r fU]t6Ȅϒ3Ȉ".ƈпɻϷΏNĢ( DMP єßΏ3GJɸѮƱʓѮȽƱʓƦ ɞKȻȬˆƤKJ rfU]t5зƤZSuS0!.˺3ˑ̨!.Ʊ ʓ#= 6 Ѳ̨̙ȐѴŷÖ̊ʬǦdruggabilityýυŜȒż̶͋grf̶͋n ƤCHK.J ̙ȐѴŷ6ˋ̝ˤЍǩˋ̝3Jπě5Ͽ˽ǩN˂C(ϱʓͯʎҐɡ ʃ}cSVgϾŨGIґHQptsRYwh0!.QqzS̚E ѨˋȌO215Ѩ̚ńIHKH3QYsQ̟ğπ5ϙ˲Hǖƺ̙ȐEx^] rpusRfhDńIHK.J @(̶̄5̓ƞȧφĥʎ̣3˕̊KJ K@/32ˋ̝ɝˏEm`ptDчϒ/J Ù7iPS ͪΘ21NĖ̊!(ͪΘˋ̝E K@/5Qo/6ũѨ0K.(m|]Їѓ̪³Ö̊m`pt3Ƴ#JÑĐƚ ıπŜ5ђ̟21Ŕ@KJ ū 3. r f U ] t g t -5- SAR News No.27 (Oct. 2014) ^̟Ѝɮ5 2010 ǟ 4 ɺ36̶̄ĉ̶͋imEƋƞ21̶͋ʬєHȾξK (rfU]tHQYsQ̟ğπı̝ȧφ5ϙ˲H 22 5rfU ]tNȻȬ!( &5ǻĵʡ¥ʰɜϕr5ȻȬNжƥυ̂ůҐ2014 ǟ 4 ɺ̂ůґ 6 4 ,5fU]t32 5rNȾЫ!.J DMP ȾЫ¥5rfU]t6 f3Ąђ!.I[2]ѡɮɷɜ!.J Ґū 3ґ ̂ů@/5Ȟʎ0!.҇ʫɎÁ PLҐ̶̄ґH3GJ iPS ͪΘ3GJ͵ΠĊ̈fU]t 5Σǥ̶͋5ђƖ5¿NKT ͪΘN̊(Oˋ̝ҐϹņÿ PLҐ̶̄ґґďτȌĜÖ̊52 ȪτʔπҐƨ̋ɏ̏ PLҐʊĮƋґґQqzSˋ̝πҐʄʃăн PLҐPVStґґ oÇʡEı̝ʬє3ƸďK( @(ÑĐƚ3. DMP Ĕʀ5ȼͨHȯ Dz!(r/6ǻ5 3.1 /У=JǡͪΘNʧ̣0!(̡τ̚ˋ̝πҐ̵ǏɗǴ TMLҐ̶̄ґґ 21I˺ϣńǽʹѠ@/ėб#JrďƖC.J 2.2 創 薬 支 援 ネ ッ ト ワ ー ク 、 日 本 版 NIH と の 連 携 2013 ǟ 5 ɺıπź̶̧͋ȣğπɋɆȠ̓ƧϢ͏KğπɋɆxpt]ʥȓćÓ ĭ!( 5xpt]6 2011 ǟĉѕǨı̝SyeȾЫƧ5ĔÁƧя/J¥ʆ̼ Иʾ5ğπɋɆʬʥʥȓ5ɂŠ͐/J &5ǻ5ͣÕɶȫNͮ.ğπɋɆxpt] ʥȓ0ŒĚNƇ̫ǣʩɛ̣2ŭƪfU]t0!.Ɩħ!( xpt]ʥ͚5§ɣ6 QYsQ̟5ğπehNƳϻ0!(ʫˢ!ʬΚNDZĭ!ź̸̶͋5ȞʎNıπŜ5Ʀ̊ĭ 3,2J(Cıπź̶̧͋ȣ¥ȃ02+.̶̄ŀ9̉ʡȧφͷŏ̶͋ȣ0ЪɈ!2H Ƌƞ̶͋ʬєEєßǨ̫/ʥȞ#Jxpt]Nʥ͚!ɻɿ2eh3Ƴ!.đK̨52 ɋɆNυ0/J DMP DğπɋɆxpt]DϢ͏ЌɣNő"!.I2014 ǟǩHğπɋɆxpt]3G+.ɡʃĂÓHȻȬK(ɻɿ2rfU]t 5ȾЫ5(C3ź̧wpt5ɂÛ21/ƭȽ3ЪɈ!.J 2015 ǟǩH6˼͏υɎˏ »ɡʃı̶̝͋ђ̟ʬʥҐɡʃ˸ NIHґ͏*I&5D0/ğπɋɆxpt]Ġ DZȾЫKJ°Ƥ/Ī̶ DMP D&5Nȯ032J 3. インシリコ創薬を担う創薬分子設計基盤ユニット K@/ͫ½!.( DMP 5ğπ˕ħ3.Sea3GJıπĐƚϢϟNȯź̧ 0!.̶̄ScSVgȧφź̶̧͋imĉ3ğπĐƚϢϟź̧wptɜϢ KSeag]w^Ϣϟ215ɋɆ̶͋Nυ+.J Seag]w^ Nυź̧ȧφ0!.6ğπ5̂Ž3JƦ̊ȌNчϖ!.ɕóNЫC.( ū 4 3̹# G3ĴΤħup[^ʈÅɹжĭegr PALLAS[3], ̪³Ö̊|m3ź-ʬʝƞΌ ˕Ȍ°ˣegr MUSES[4], ƉѮ̣Zuȼͨegr LAILAPS 21Nђ̟!.Ю̊!. J PALLAS 6m|]ЇʥЩ5ħEup[^QbhNŔBƉ5up[ ^ʈÅNĴΤħ̣3ʠϠ!̨̣5m`pt3ͯŏ!ǽJÑĐƚĭŏ˹5up[^3ɹж2 ʈÅNϔď#ȤģN#J ǽHK(ʈÅ3G+.ɔIJ2!6ɔ̢ĭŏ˹3Ƴ!.up[ ^NυЧǛ5up[^gaQE X ʥЩ/ͯʥʦǬM+.Jĭŏ˹05ąɻÓ ͊213G+.ɔijæ͆ǩ@/ͰIОAH3&5ǻ5ͰIОA/6̪³Ö̊ϡУƚN̊ (ʬʝƞΌ˕Ȍ°ˣ MUSES NØŽŏDJ m|]ЇʥЩEɠ̳5ZuȒżϺƮ2 Žŏ6MUSES ĥʎ̣)Ȓżƺ2m`pt5Žŏ36Ė̊Ѩ! &5G2 Žŏ5ɹǻ5ͰIОA3Ė̊/JG33.2 /У=J FMO-PBSA ˏNђ̟¥/J LAILAPS 6ĸ/62Ɖ5ϙ˲H5ZuȼͨˏNͭAŏM%JȤˏ/Iп ĐʥЩʠͨ2D/3D 5ѺÎʠͨ2D/3D 5ʬʝƞΌ°ˣNͭAŏM%.gaQNʧ˦ĭ!.ď Ġ#J0/J ˺3 3D dz˻PS3GJʬʝƞΌ°ˣˏ6ȟɜϕ3ђ̟! (Ȥˏ/J[5] LAILAPS 6m|]ЇʥЩ˳Žŏ3DƦɞňΚ/̴ɮѓ/ϟ͘/ }ptȼͨΚĠDƋ(C͟ƽ̚s3Ƴ!.πĥN̹#¢̑Ĕ5QsRx]oŅƫ Ó˕Ȍĭě5̟ϔ͕3Ͽ˽!.J[6] @(smg3є!.6ǔЀĭŏ˹sm gChEMBL/PubChem ͕5ĄąsmgŏȞƫɩĭŏ˹smgNͱŏ!S eag]w^̊3ĚĎ̄!(ŏϟ 1 ø 1 ijĭŏ˹5ͱŏsmgNɕó!.J -6- SAR News No.27 (Oct. 2014) 5smg6чĽƚɔdruglikenessȅйʥЩͥʀ3G+.ɔ̢Yrb3ĐѺ K.ISeag]w^NυѢ36̨̣3Ȉ".15͙ŪNʠͨ#J͛Þ 2ɉÖ/зȬ#J0/J ū 4. ğ π Đ ƚ Ϣ ϟ ź ̧ w p t 5 S e a g ] w ^ ȧ φ 3.1 HCK 阻 害 剤 の イ ン シ リ コ ス ク リ ー ニ ン グ と 設 計 ȋȌ҅҆Ȍ̡τ̚6Ĕ̟5Žŏ36ɠƜ5ˋ̝π3GJƯϛňΚ2ŽŏƉ҅҆¥ 3̡τ̚ǡͪΘʷ+.JŽŏIĊ̟#J0ĥʎ̣2ˋ̝6ũѨ/J ̶̄5̵ǏH 6̡τ̚ǡͪΘ0ЩτǡͪΘ5ѓ5̟̂иÊƚ5ʽЖϛʌ3GIHCK NŔB,5и Êƚ̡τ̚ǡͪΘ3.ɻȔ3̟̂ɦ#J0N͍ʰC([7] 5̳ϔNŅ .̶̄ DMP /62010 ǟH HCK Nm`pt0!(̡τ̚ˋ̝π5ȼ̶ͨ͋NђƖ! ( HCK 6SRC family 3ǂ#J kinase /I#/3m|]ЇʥЩɠ̳јƩěȒż0D 3ϺƮ/I&KH5Ȓż3ź-.PALLAS 0 LAILAPS 3GJSeag]w ^Nυ+(ͯʎʊƋ5ğπXSyeim5S[8]HзȬ!( ĭŏ˹ RK-9024466 HCK 3Ƴ!. IC50: 7.7 nM 5јƩ˕ȌN̹!( Ґū 5ґHCK 0 RK-9024466 5ϏŏÓʥЩN̶̄5ʩDŽH5^ϛʌ!&K3ź-(ϢϟNυʽЖ̣ПШ3 IC50: 0.43 nM Nȴ, RK-0020449 Nϔď#03Ȟġ!( RK-449 6̡τ̚ȐΏ̌ʉ5ǡͪΘE&5ǡͪΘNƃʸ%Ā̘ ĂTg3ͅʟ!(ħ ˹s3.҇ĥʎN̹![9]̂ůΣǥϦ҃<œ.ђ̟NЫC.J 3.2 Pim1 阻 害 剤 に お け る Activity Cliff の FMO-PBSA に よ る 活 性 予 測 Pim1 6|ΞH̟ϔK( Ser/Thr kinase /ISTAT |gTUS5˕Ȍĭ͕NЧ!. ̡τͪ̚Θ͕5ƃʸ0̈Ɯ3.чϒ2öN!.JȋȌ҅҆Ȍ̡τ̚5ğπm`pt /J ɗп̓ƞ̫m`ptm|]̶͋^3.̶̄5̋ÄH5^̟ ʚ!ʊƋяшH5^05ąő̶͋3G+.јƩě5Seag]w^0&5 -7- SAR News No.27 (Oct. 2014) ū 5. HCK ј Ʃ ě 5 S e a ğ π ǻ5ϬƸĭǁђNυ+( &5Я͆3,.6ͦѮ5рŏDIϨ!У=2PALLAS 3G+.зȬ!(up[^ʈÅ3GJSeag]w^3G+.IC50: 400 nM ͆ǩ 5јƩěN̟ϔ![10]&5ǻ5Ϣϟ0ŏȞ3G+. 1 nM ͆ǩ5јƩě@/ėб!.J[11] 5 Pim1 5јƩěϢϟ3.ʥЩ5ƹ2Ƈĭ3G+.°ʀ!2Ƌ2˕ȌƇĭҐM FJ activity cliffґNͮ҃!( ū 6 5Ǒï3ĭŏ˹5ʥЩ0˕ȌN̹#ŋ5 5-6 ̆͠5 1 æ5˱͎ͧͧ3ƇMJ03G+.ɹƋ/ 200 ç͆ǩ˕ȌÑ!.J 6 ĭŏ˹5* 4 ĭŏ˹6ϏŏÓ5 X ʥЩϛK.J>0O1ʥЩ6ő"/IǼʉ5ĐƚĠŽ3 ź- MM-PBSA /6log IC50 05 R2 0.59 0Ñ̪є!̹2+( &/KH 5ϏŏÓʥЩҐŀ9 X ʥЩ5˳ 2 ĭŏ˹5sʥЩґN QM-MM 3G+.Vx\ɹ жĭϟ͘!FMO 5 IFIEҐ^tѓ̪³Ö̊Vx\ґ5ŏϟë0 MM-PBSA 5 PBSA ѲпĐNŏM%(ëNϟ͘!log IC50 05̪єNϔ(0LR2=0.92 0̪҇єN̹!( Ґϲɗȩ͉˦ó¥ґ ʃ̶͋3.6m|]ЇҔZuϏŏÓ5ʥЩ5ŜЇчϒ/+( X ʥЩ&5 D5EĐƚĠŽ/Vx\ɹжĭ!(ʥЩ/6MM-PBSA /6Ͻ5̪єFMO-PBSA / D R2 / 0.3-0.5 ͆ǩ/I¼Ŧ5G2ʥЩƇĭ5ƹ2ĭŏ˹ipt3J activity cliff 5°ˣ/6˺3ʥЩ5ŜЇчϒ/J0̹şK( !!@) 1 m`pt/5ͯ ʎ/IsmiptDƹ5/¼ǻ6Ϗɔ5̕2J͇Ѻ5m`pt/ 10 ĭŏ˹ 5ipt/5ʠϤN΅IТ#°Ƥ/J @(PB (Poisson-Boltzmann)Ѳ3,.6Dz̶͋Ƨ 5ˢлH3G+. FMO 3G+.ϟ͘#JɝˏDђ̟˟A[12]/J1 æ5ϟ͘ëNǽJ( C3 FMO ϟ͘NÔŦ΅I#ȄϒIϟ͘ɮѓѭǛ3я 5пĐ5ĥ̀ĭ͕D υщƚĭƞϟ͘/ʥȞK( FMO-PBSA ˏNơȞ%( -8- SAR News No.27 (Oct. 2014) ū 6. Pim1 5 Activity Cliff 5 FMO-PBSA 3 G J ° ˣ 4. お わ り に 超 分 解 能 FMO 構 造 決 定 法 へ の 期 待 QYsQğπ3JSeag]w^Ϣϟ5ǸĞ6ѭǛ3Ƌ ƋȤώπÇ ʡ5G3˹щ3G+.јƩě5ȼͨŏȞNυ0ũѨ/J(CÑagt/Ƌ2 chemical space Nȼͨ!ŏȞ#Jĭŏ˹NͰIОB06чϒ/J ́(*5̶͋Ƨ/6 Ʀ̣̊2ȧφҐPALLAS, MUSES, LAILAPSґ5ђ̟00D3ʮ¢Á5ɹý͐ȧφҐFMO-PBSAґ 5ђ̟3DńIͭO/J ˺3͞ǩ5҇ͯŏϘśȌ°ˣ/6Ǽʉ5ŇĈĠŽ/ÖȞ!( sNѪƚƭǩ3жŏ%.ˆƤ#J X ʥЩ/6 IJĐ/J ̂ůɡʃƋƞ5̿˫̽ ȡƋƞ5̋¥H00D3ɹĔH FMO 3G+.ʥЩˆƤ#JȤˏҐFMO ЊĐϛΚʥЩˆƤˏґ Nђ̟!.IV]c215ʮ¢ÁƋϕʨϟ͘ʬ0ЪɈ#K7PDB 3̠эK.JĂm |]ЇʥЩ5ĊˆƤDƊ/62 ɡʃ̟5¢̑ʧ˦5ʥЩϛʌȤˏ3̟ǁ#J0NʀǺ! .J ϵК ʃ͉5Ÿ͔3(IĶĠ()@!(̶̄ DMP 5˜ϔ͑Ǥʦâ̭̋ŁƚʦɡʃƋ ƞ5̿˫οý̈3Ǿ̺̎!@# ĿΎɗ˽ [1] Robert, K. Nature Reviews Drug Discovery, 9, 867-882 (2010). [2] http://www.riken.jp/research/labs/dmp/ [3] Sato, T., Honma, T. et al., Bioorg Med Chem, 20, 3756-67 (2012). [4] Sato, T., Honma, T. et al., J Chem Inf Model, 50, 170-85 (2010). [5] Sato, T., Honma, T. et al., J Chem Inf Model, 52, 1015-1026 (2012). [6] Okada-Iwabu, M., Kadowaki, T. et al., Nature, 503, 493-499 (2013). [7] Saito, Y., Ishikawa, F. et al., Sci Transl Med, 2, 17ra9 (2010). [8] http://www.ocdd.u-tokyo.ac.jp/ [9] Saito, Y., Ishikawa, F. et al., Sci Transl Med, 5, 181ra52 (2013). [10] Tsuganezawa, K., Tanaka, A. et al., J Mol Biol, 417, 240-52 (2012). [11] Nakano, H., Nagano, T. et al., J Med Chem, 55, 5151-64 (2012). [12] Watanabe, H., Tanaka, S. et al., Chem Phys Lett, 500, 116-119 (2010). -9- SAR News No.27 (Oct. 2014) ///// Cutting Edge ///// S e a ğ π 3 J FMO ˏ 0 ŗ М ź ̧ ȧ φ 5 Ы ʳ ɡʃƋƞʋȡʴƞп̿˫ ο 1. は じ め に 1999 ǟ3Į˘śƎɐȸH3G+.ɂʚK(^tĐƚВаҐFMOґˏ[1-4]65 10 ǟѓ/Ƌ̟ǁ!̈Ó҇Đƚ͠5̪³Ö̊ϛʌq0!.Ƥ̰!,,J щƚĭƞϟ͘ 3G+.m|]ЇEZuϏŏÓĂÓ5Ѫƚ˻ȗǽHKJ5ɝˏ6˺3ğπĐш3 .6ɤH Structure-Based Drug DesignҐSBDDґ<5˕̊ʀǺKώπÇʡ3GJĖ̊ DЫO/J[5-8] FMO ˏ3є!.6ɹС5ɡʃĭƞÉ5ȒżĭƞпÉϩ3Ŧ3ˢ+.˺ ѦK.J0HDˑ̨ǩJ[9] FMO ˏ6m|]ЇNQyфʷźĸÐ215^t3ĐĞ!ŗМ5^ tH5̆ƂѬѪre¥/^t5yҔEnS5Ѫƚ˻ȗNϛĐƚ ĂÓ5Ѫƚ˻ȗNĊʥ͚#JСÎȤˏ/J ¤ēĭĥ̀GЊ¤ēϟ͘ʬ3œ.I, ˃̊ȌD҇ ÔGID҇Ш҇͞ǩ2ĂѪƚϟ͘Ȥˏ/J03̒@H$Đƚѓ̪³Ö̊5 ʣȉNАϐ!.J(Cĭƞ̣̩ϙ3ˌ+(ȒżǽHKJ5ɹƋ5DZA/L FMO ˏ 5(C5ϟ͘^6ϏɔJʃ͉/6ȟ5̶͋^/ђ̟¥[10]5 ABINIT-MP 3GJğπĐш<5ǁђ3,.ʣϯ#J FMO ˏ6̪³Ö̊5ϛʌ3.ʢC.ɻ̊2ɝ ˏ/JňϖĭϛʌʬΚNûƦ%J0/H3ɻ̊Ȍƃ#(CƵ̊ňϖĭ GUI / J BioStation Viewer 5ђ̟D͊ʢ̣3ЫC.J 2. 相 互 作 用 解 析 ツ ー ル と し て の FMO 法 FMO ˏ/6ĐƚN^t3ĐĞ#J0&!.^tѓ5̪³Ö̊ Nϛʌ/J0Ƌ2˺ȁ/I&KH0@Àŏ0Ƌđ/J ^ t̪³Ö̊5źʃĸÐ25/ˑ̨!(̪³Ö̊ǽHKJG2ĐĞN!.0 /ǻ5ϛʌEIɩ2J ĐĞ3Ѣ!.͞ǩʠϤK.J56sp3 ˱ͧN Bond Detached AtomҐBDAґ0!(ĸͯŏ/5đɛ/J03ˑȔ!&KÂƈ5Žŏ36ʠϤ!.H5 Ė̊NīC#J ЧǛ6m|]Ї6QyфĸÐ/ĐĞ!Zu5ÑĐƚĭŏ˹6Ă ÓN 1 ,5^t0!.ψ̂#J0Ϊϟ͘͞ǩ5ͯʎǽHKJ ĭŏ˹5ĐĞEQ yфïю5ĐĞ3,.6ƉÓ FMO ˏ[11, 12]̊HKJ 2.1 IFIE と PIEDA ^tѓ5̪³Ö̊0!.ɹD͛Þ/Ϊ̊HKJ5^tѓ̪³Ö̊V x\ҐInter-Fragment Interaction Energy; IFIE@(6 Pair-Interaction Energy; PIEґ/I KH6ĂVx\5͘ď0őɮ3ǽHKJ ŅƫÓҔZuϏŏÓ3Ƴ#J FMO ϟ͘6 IFIE NVx\ȵʧ0!.ZuҔʷźѓJ6ʷźőƆ5̪³Ö̊NƤщ̣3ϥÝ# J0/J(Cϲ̣̄2up^sdS3ж!.J Ù0!.ū 1 3ΖO5m `pt/J EGFR oe[vj0јƩě erlotinibҐšŜŒmi{®ґ05ϏŏÓʥЩ 3Ƴ#J FMO2-MP2/6-31G*5ϟͯ͘ʎN̹# Ǒ5͏Óū/6IFIE 5ë0͏ÓʥЩ5є ßNΎư#J0/ŋ5 IFIE map /6^t5ĂͭAŏM%3Ƴ!.ǽHK J IFIE ëN͵Έ/J3 distance matrix 0ʽЖ#J0/҇ʮʥЩ0̪³Ö̊5єЪÀDň Κ/J ,@I X ͯɳʥЩϛʌ͕3G+.ǽHKJ͏ÓʥЩH6ЎѧȒżɨH32 Iˀͧͯŏ215̪³Ö̊D°ȓ#J0/J&5ͯɳʥЩ3Ƴ!. FMO ϟ͘Nυ 0/Ƥщ̣2̪³Ö̊ȒżNÀĢ#J0/J H3IFIE N 4 ,5Vx\ȞĐҐѬѪVx\; ES·Ʉł̟Vx\; EXѪδ ͅħVx\Ғ҇ʮѲ; CT+mixĐɑVx\; DIґ3ĐĞ#JɝˏPIEDA ҐPair-Interaction -10- SAR News No.27 (Oct. 2014) Energy Decomposition AnalysisґĮ˘Fedorov H3G+.ɂʚK.J [13] Erlotinib 6 ̖ˀ̣2ƣΚźNƉŔA[vj0ˀͧͯŏ!.J56[vl̆5fпĐ) /IʃɔDƺ2PIEDA ϛʌHˀͧͯŏ3Ģ.Ѫδ5ͅħNË+( CH…O ˀͧ ͯŏE CH/̪³Ö̊3G+.̪³Ö̊ƠƤĭ!.J0ɨH32+( ˺3ĐɑĠN §ȞĐ0!.Zu0̪³Ö̊#JʷźƉɔƜů!.JҐū 1ґ ū 1 EGFR oe[vj0 erlotinib 05̪³Ö̊ϛʌ Ǒ6 IFIE 5͏Óňϖĭū/I ҍΫ/̹#Zu3Ƴ!.Ŏʷź5̪³Ö̊5DZNЈѫΫ5˭/ψ!.J ŋ6 IFIE map G9 distance matrix6 PIEDA ϛʌ[14]3GJ ESEXCT+mixDI ŎȞĐ<5ĐĞN ψ# Vx\5ĸÐ6 kcal/mol 2.2 多 体 FMO 法 と リ ガ ン ド 分 割 PIEDA 3GJVx\ȞĐ5ĐĞNυ0̪³Ö̊5ȌЇMJ(C SBDD 3GJϲ ̣̄2ğπ3Ǹ͏, ɝ/Ƌ2ĭŏ˹NǢ,5^t3ĐĞ!пĐʥЩ5̪³ Ö̊NϥÝ/J0Ǹ͏,0DJ ƣΚźĸÐ5̪³Ö̊NϥÝ#Jɝˏ0!.6MF J^tĭŏ˹ҐFragment-Based Drug Design 3J^tґ5G2ƣΚź͆ ǩ5ƹĐƚ3Đ.!@ɝˏ0[6]Җ,5ĭŏ˹N FMO ˏ5^tĐĞĎ̄/Đ -11- SAR News No.27 (Oct. 2014) JɝˏJ[12] ǻΏ5Ù0!.SVdTSg5ySwnjҐNAґ0 zanamivirҐšŜŒd®ґ5̪³Ö̊3.6£ȌSX/JZuĂÓN@0C JGI6ʬΚпÐ03^tĐĞ!(ɝŗŪ5Qyфʷź05̪³Ö̊Nжđ3 ϥÝ/J ū 2 6 zanamivir N 4 ,5пĐʥЩ(1)~(4)3ĐĞ!( FMO4-MP2 ϟͯ͘ʎ/J ϽѪδNȴ,(1)0ʱѪδNȴ,(2)5^tŗМ5δѪȌQyфʷź0Х5ƠƤĭ̪ ³Ö̊N!.JʦƚE¥Ȍ^t/J(3)(4)0ˀͧͯŏ#JŗМʷź05ѓ3ƾȣ ̣2ƠƤ̪³Ö̊JʦƚNɔẹ̈3ϥÝ/J 5G2Ȓż6ƣΚź5sdS3ɻ̊ /J Ï!GIͪ^t<5ĐĞ6ϟ͘͞ǩNι0#032JȍKJ 1 ,5ƳĎˏ65Ù5G3ƉÓύʱ FMO ϟ͘[11]N̊J0/ĐĞ!(Zu5Ѫƚ ˻ȗ5®KNύʱ!ĭŏ˹0!.5ȌЇNɇ202ϛʌ#J0/J[12] Z uͯŏcSt5 IFIE 3є!.6sp3 ˱ͧ/5đɛNυ+.K7ƋȮ6 FMO3 ύʱ/ĴƤщ ̣2ëǽHKJ0̣ͮ҃3̷CHK.J -40 40 ū 2 SVd NA 0 zanamivir 5 FMO4-IFIE ϛʌ Ϋ5ψ̹6ū 1 0őʦҐĸÐ6 kcal/molґ 2.3 相 互 作 用 解 析 の 流 れ IFIE g5̪³Ö̊ϛʌ36¿3D VISCANA [15]215ĭŏ˹]gm^ȤˏD JABINIT-MP 36Ва/H3Ϩͪ2ϛʌN#JȤˏ 2 ,ƦϊK.J 1 , 6ˀͧͯŏ͕5Ѫδͅħ̪³Ö̊Nȥ0/J CAFI [16]D 1 ,6 CH/ πEπ/π215 Đɑ̪³Ö̊Nȥ FILM[17]/J У5 PIEDA 5ŎȞĐ5*CT ѲN CAFIDI ѲN FILM 3G+.GIϨͪ3ϛʌ#J0Sf32JҐϨͪ2ɝˏϲ3,.6ĿΎɗ˽N Ŀ˵K( @(@/D̕2J^tѓ5Ва̪³Ö̊/J03ˑȔ#Jґ K@/3ď.(ϛʌȤˏNͷŏ#J0ū 3 3̹#G2ϛʌ5˖Kϔ.J @ $6ЧǛ5 IFIE ϛʌ3G+.͵Έ̣2ϛʌNυZuͯŏ3чϒ2QyфN˺Ƥ#J /^tĐĞ5͞ǩDoUp]#J Ȅϒ3Ȉ".ƉÓ FMO ϟ͘NńIāKJ PIEDA 3G+. IFIE 5Vx\ȞĐNĐϛ!̪³Ö̊5ȌЇN̄ϛ#J ˺3 CTDI ȞĐчϒ2ʷź3є!.6CAFI E FILM ϛʌNυƣΚź5Ва15G2̪³Ö̊ N!.J5NɨH3#J #J0/ͯŏ5чϒ2пĐ3WYg!.0 /J ƻĂ.5ig3.ȵʧ02JɔëǽHKJ -12- SAR News No.27 (Oct. 2014) ū 3 FMO ˏ3GJ̪³Ö̊ϛʌ5˖K 3υ>1Ϩͪ2ȒżǽHKJ 3 FMO 法 を 用 い た 構 造 精 密 化 У5G3ŅƫÓҔZu5ϏŏÓʥЩK7̪³Ö̊ϛʌ6>?ˆ@+(Ȥѳ/ υ0/JGI͞ƭ2ϛʌ5Ѣ3чϒ32+.J5ʥЩ5͞ƭĭ/J ˺3 ZuŗМ3є!.6G>1҇ĐϛΚ5 X ͯɳʥЩϛʌNυM2ћIIJĐ3ãѶ/ JʥЩNƦ̣҃3ǽJ06Ѩ! K@/5ȟ5ʠϠ/Dup[^ʥЩ3.Z uпĐ5ʥЩN QM ϟ͘/ˆC̩#0/ͯŏVx\ɔçDƇĭ!(I͞ǩ IJ Đ2ʥЩ3Ƴ!.Яĝ2ѪδͅħϬЉKJ021ɑϔK( ͞ƭщƚĭƞϟ͘3 .6͞ǩ IJĐ2ʥЩ6Ϯ+(ϛхN¡JȍKJ &/ɹС6 FMO ˏ3GJʥЩ 5͞ƭĭ3ĠNāK.J[18, 19] 3.1 構 造 最 適 化 の 重 要 性 ʃŌ5 Perspective/RetrospectiveҐʃѓý̈ґ/Dͫ½K.JG3QM ϟ͘3GJZ uŗМ5ʥЩɹжĭĭŏ˹5˕ȌN°ˣ#J/ˆƤ̣32J0J ˺3 FMO ˏ3 GJVx\ϟ͘E̪³Ö̊ϛʌNυŽŏ36̊JʥЩ0 FMO ϟ͘5{g Ƌđ02J @(}gof5tĭ˻ȗ5ˆƤ3DʥЩɹжĭ6ɻ̊/J }go f6у͕ͧ5ʬΚ̟̂3ßJчϒ2ʷź/I&5tĭ˻ȗ6Ľƚ/5łȈ Ywh3ˆƤ̣2ǸĞNʎ(#(Cm`pt15tĭ˻ȗ3J5N̳J0 6чϒ/J Vgt`ŅƫÓ5Zuͯŏ3J}gof5ˀͧÀĢ˻ȗNϥÝ! (ÙNū 4 3̹#ҐZu6 17β-estradiolґ ¥Ȍ˻ȗҐHIDHIEґG9tĭ˻ȗҐHIPґ 5 3 ʥЩ3,.FMO ʥЩɹжĭNυ+(0LHID /6Snl̆ͯɳʥЩ5Ѯ H$KHIP /6ˀͧͯŏŅƫÓ5 Glu 5§ю5Ywź<5tͅħЉ+. HID 32+.!@0Đ+( H3 HID 0 HIE 5ɹжĭʥЩ/6ˀͧͯŏ3JѪ δͅħ5œ̕2IHID GID HIE 5ɝZuͯŏVx\ 10 kcal/mol ͆ǩƋ 2J0M+( Ǽ+.Zuͯŏ3.6 HIE ˻ȗùÐ/J0ΎHKJ ŧA3ū¥5 CAFI 3GJѪδͅħ5Ва̪³Ö̊ϛʌ/6ƔDz2Ɂ÷NǽJ(C36 QM 5ʥЩɹжĭȄϒ/+( -13- SAR News No.27 (Oct. 2014) ū 4 FMO пĐʥЩɹжĭϟ͘3GJ}gofˀͧÀĢ˻ȗ5ϥÝ ҐқɹжĭʥЩ5ʽЖқCAFI 3GJВа̪³Ö̊ϛʌґ 3.2 FMO 超 分 解 能 構 造 解 析 FMO ϟ͘3GJʥЩ͞ƭĭ5D 1 ,5QoFMO ЊĐϛΚʥЩϛʌ/J FMO ϟ͘Nυ(C36ź32J X ͯɳʥЩĖ̊/J0ĚɂʈÅ/IK@/6 RCSB Protein Data BankҐPDBґ/ĄђK.JʥЩNĖ̊!.Vx\ϟ͘EʥЩɹжĭ Nυ+.( &K3Ƴ!. FMO ЊĐϛΚϛʌ06X ͯɳʥЩϛʌ5ig3̩Ƚ FMO ϟ͘NĖ̊!.ѪƚƭǩȒż͕Nύơ!ʥЩˆƤ5͞ǩNœ%G0ȧφNȵ!̂ ů̄ĭƞ̶͋ȣ5ʃѓ^E̽ȡƋƞ5̋¥^0ąő/̶͋NЫC.J ˺3 ZuŗМ5сǪˆƤ5҇͞ǩĭEaW5ĺɻ̀5͞ƭĭˀͧĽƚ5ÐΆˆƤ3є !.X ͯɳϛʌ5ĐϛΚ 2.0ҟ3.0 ͆ǩ5sm3Ƴ!.DƦЇ̣3GI҇ĐϛΚ5Ʀ ҃smNǽJ50ő͕50бȞ/J0N̨ʧ3!.J ū 5 Vgt`ŅƫÓ3JZuŗМ5Ѫƚƭǩ0 FMO ɹжĭʥЩ -14- SAR News No.27 (Oct. 2014) FMO ЊĐϛΚϛʌЯ͆/̊J FMO Ѫƚƭǩ6Đƚ5ĭƞͯŏEĐʢѪƚѩ5ʒГȌ 3ƳȈ!.J ý5Vgt`ŅƫÓ5ZuŗМ5ɹжĭʥЩ3J FMO Ѫƚƭǩ NɁ.AJ0Ґū 5ґĭƞͯŏ3ˌ+(ѪƚƭǩĐǕǽHK.IElectron Density Server ҐEDSґ3̠эK.J X Ѫƚƭǩ0DŏΦ#J @( MP2 5ɹжĭʥЩH6 17β-estradiol 0ˀͧͯŏ#J Glu 05ѓ3tąɻϙˣKŗМ5Ѫƚƭǩ˭2+ .J0M+( ЧǛ5ˀͧͯŏNdzȞ#J His 06ɨH3̕2+.J[19] KH 5ͯʎ6 FMO ʥЩɹжĭ5ŃʇʥЩƦ҃±Ʀ0жŏ!.J0FMO ѪƚƭǩʢC. ƔDz/J0Nψ!.J ū 6 FMO Ѫƚƭǩ3GJ crambin ĺɻ̀5ϥÝҐTyr29ґ H3Ʀ͌ѓ/5Ѫƚƭǩsm5ɔëʽЖDЫC.J ū 6 6 crambin 5҇ĐϛΚʥЩ Ґ0.48 PDBID: 3NIRґ5*3 ,5aWJ Tyr29 3,. X ƭǩ0 FMO ƭǩNʽЖ!(D5/J[20] ŎaW3Ƴ!.ϟ͘K( FMO ƭǩNжđ3˝ŏ #J03G+.Ʀ҃ë3С-.JʦƚMJ ¼ǻ6K3ϥÝєɔNƸā!ĺɻ̀ 5ɹжëN˂CJ032J ¿3DFMO ƭǩN̊( 2Fo-Fc G9 Fo-Fc p5Ƹā2 13,.̂ůЫC.J 4 おわりに IFIE NVx\ȵʧ0!(ZuҔʷźѓ̪³Ö̊5ϥÝ6 FMO ϟ͘5ƠƤ̣2Ė̊ˏ /J X ʥЩϛʌ3GJЎѧȒż3Ģ.щƚĭƞ3ź-(Ƥщ̣2̪³Ö̊ȒżNǽ J0/J(Cğπ̶͋Ώ5ɝ36ɭѭm|]Ї0Zu05ąͯɳʥЩńK (H@$6 FMO ϟ͘Nυ̪³Ö̊ȒżNńǽ!.AJ0ØɝNīC!(Ґup [^ʥЩ3.Dőʦ/Jґ FMO ϟ͘6¼E̶͋Ƨ5 PC ]gmJ6waQ 5|ka/DȤЕ3ϟ͘/J>1БС32+.IĔȃΏ/DØE# GUI Dɕó K.J ƋI2ʥЩ͞ƭĭN!2.DΩ̣2s^ktN̊(ʥЩ5ĚĎ ̄Nυ+.7ƤỌ̏2Ȓż6ǽHKJ(C&K@/ȔϷ!.2+(̪³Ö̊5чϒȌ 3ʿÀK(IʥЩHǽHKJÃϯ3̄ϲ̣2ϋÀN¡J0/(Ipt 6Ƌ6$/JҐFMO2-MP2/6-31G NȾƒ#Jґ ̂ůIFIE smg5ʥ͚D ʠϠ¥/J GI͞ƭ2̪³Ö̊5ΎưEĐƚsdSJ6ĭƞłȈYwh5ϛɨ5(C36G IƋϕʨ2ϟ͘Ȅϒ02IˑȔ˜ϒ˂KĴ˻/D2I5Ϩͪ2ϛʌ@//J qɀ+.J @(¼Ŧ6ϜK2+(ˀś5Ţѷ3,.DĐƚsEЪͳ˧Ƙ s3GJ̶͋ЫO/J[21, 22] ¼ǻ6Ɖ5̶͋ΏũѨNȖ".JZuŗ -15- SAR News No.27 (Oct. 2014) М5͞ƭʥЩˆƤEłȈ¥ȃ5tĭ˻ȗ21щƚĭƞϟ͘NǒA3˕̊!(Ė̊ˏN̷ ͏#J=̶͋NЫC.(0Ύ.J ϵК ʃ̶͋5ȾЫ3ĶĠѱ@!(̄ĭƞ̶͋ȣ5ʃѓþЂý̈ˢлijҋĹƆˇDŽ×̈Ĺ Ɔ̽ȡƋƞ5̋¥ȞĈý̈͏ɐƋƞ5ɿɺ̼Ȇý̈A$>Ȓżͷ̶ʖǬÉ̻5̤ʦ3Ȗϵ ̎!@# @(ʃ̶͋6ɗп̓ƞ̫HPIC Ƞ̓^5Đш 4ʮ¢ÁD5-I 5ɋɆNŅ@!( ĿΎɗ˽ [1] Kitaura, K., Ikeo, E., Asada, T., Nakano, T. and Uebayasi, M. 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Explicit solvation modulates internal- and inter-molecular interactions within DNA: electronic aspects revealed by the ab initio fragment molecular orbital (FMO) method. submitted. -17- SAR News No.27 (Oct. 2014) ///// Cutting Edge ///// YN̊(ɜϕQu`ŅƫÓȳȪπ5ğώ ʊĮπ̓Ƌƞƍ̋Ąϕ はじめに grSu6&KH5ʥЩ5¥ȃ3Λ˧Ȍ5҇˱ĭˀͧ҅ʙNɻ!.I˺̕ ̣2grSuŅƫÓ3ͯŏ!̈ÓʬΚNľƭ3ĘǾ!.J grSuÖ̊Nɻ#Jıπ Ŝ6DZĠ,ƉDž3Ö̊N̹#0HǜǤˋ̨̝̣/Ø̊K.IgrSu҅ʙN ŔBD50ѭgrSuʥЩ5җ,5mS3ĐѺKJ ĚΏ6ŅƫÓ05DZ̖ˀȌ̪ ³Ö̊N˾ǽ/JĖ˲JŅƫÓ5зȬȌ0˲/ŢѷNȭ.J ǻΏ6҇ ŅƫÓзȬȌN˾ǽ/JD55grSu˺ɻ5Ǎ̖҇ˀȌʥЩNʨê#J0 Ѩ!ŅƫÓ05DZͯŏNǽJ06ƫɩ/2Ґū 1ґ ̖҇ˀȌN̹#Ǎ҇ĭŏ ˹0!.QnmȶHKJĭŏ˹5ʥЩG9ŏȞ0˲/grSuĭŏ˹ 5̖ˀȌʥЩ0!.6ɹж062 &5G2¥/˱ͧŔɻTͧ]gm5,0 !.ŇH̳HK.JY3ˑ̨!( Y6˳ʬĭƞΏN¥ȃ3Tͧ¥ ȌƚύЍ̝ˏ<5Ȉ̶̦̊͋O32K.( 1)ȟ6Y5ʮúʥЩG9 ̖҇ˀȌNğπ<Ė̊#=ẓ̸́2ğπȼͨHıπèύĭŏ˹5ğώ@/ǜǤ̶͋N ǁђ!.( /6YN̊(ğπ̶͋5¥/Ě͏Ο̞5ʘˋṆ̨0!(Q u`ŅƫÓҐARґȳȪπ5ğώ3,.У=J 2), 3) 図 1 代表的なステロイドホルモンの構造と testosterone の三次元構造 新規疎水性ファーマコフォアとしてのカルボラン Y6²IJѮÓʥЩ5 12 æ5ѱ˲3 2 ,5˱ͧĽƚ0 10 æ5TͧĽƚÐΆ!( ʥЩNȴ,ĭŏ˹/Ă.5˱ͧ0Tͧ3ˀͧĽƚͯŏ!.J(Cƈï6 12 æ5ˀͧ Ľƚ/ϓMK.I˱ĭˀͧ0ő͕5̖҇ˀȌN̹#Ґū 2ґ @(ĭƞ̣3ʢC.ƠƤ/ I2 ,5˱ͧĽƚ5ÐΆ5в3GIXtm|3 ͇5̕ȌÓƜů#J0 Hʮúj0DÙHKJ ɷ3˂ʗłȈE˂ѪƚłȈъǂϜƘ3GJYp ^łȈ21ЧǛ5ɻʬŏȞłȈж̊/JÆȔ5˱ͧĽƚETͧĽƚ3зỌ̃̄3 ΆɄźNƸā!(ĭŏ˹<ϬƸ#J0ňΚ/J 1) 5G3ŏȞ͞ώG9âƜ@ /ЧǛ5ɻʬĭŏ˹0ő͕3ȥ0/J0Hȟ6Yıπĭŏ˹5̖ ˀȌPaWQ0!.Ė̊/J0Ύ( ˺3̖҇ˀȌ0˺ạ̏2͏ÓʥЩNɻ# JgrSu҅ʙ5пNY/ΆɄJ0/ѭgrSuʥЩNɻ#Jĭŏ˹3 DZ̖ˀȌ̪³Ö̊NÀ¡!grSuŅƫÓҔZuϏŏÓNƠƤĭ/J0Ύ ( 図 2 カルボランの構造と 3 種の異性体 -18- SAR News No.27 (Oct. 2014) 前 立 腺 癌 の 治 療 を 目 的 と し た カ ル ボ ラ ン 含 有 AR 拮 抗 薬 の 創 製 Qu`6AR <5ͯŏN½!̏Ȍ5̈̄ʬΚE͖Γ5̟б21Nà#̏ȌgrSu / J ̈ Ó ĉ Q u ` 6 testosterone Ґ TS ґ G 9 & 5 Á ϵ ˹ / J dihydrotestosteroneҐDHTґ/JҐū 1ґ DHT 0 AR 5ͯŏʦǬ6ąͯɳʥЩHɨH02 +.J 4) DHT 5Ywź6 AR 5 Arg752 G9 Gln711 0ˀфź6 Asn705 G9 Thr877 0ˀͧͯŏNdzȞ!.IgrSu҅ʙ6KHˀͧͯŏȌƣΚź5͌ѓсΆ0 AR 5̖ˀ Ȍ_pt05̖ˀȌ̪³Ö̊3є¡!.JҐū 3ґ AR 6ʗĉŅƫÓ/IZuͯŏ Ѵŷ3̈ÓĉQu`ͯŏ!(ǻ͇5aQ]om0ДċŧƚϏŏÓNdzȞ# J0/Qu`Ö̊N̟Ʌ#J 5ɮAR 5 12 ̨̔5<p]gҐH12ґQbwg tсǪ32J0aQ]omͯŏ!ДċàЫKJ ɝZu5ͯŏ3GI H12 QbwgtсǪN0K2Žŏ6aQ]omͯŏ/$ŅƫÓ5˕ȌĭȨĘ K&KH6Qmbwgt0!.ʬΚ#JҐū 3ґ Сǟ̻É5҇ҏĭ0ѽ̈˕5ʯ͜ĭ3ËĚ͏Ο̞5·Ȑ̀0ʶ¶̀5ȋˬ2ƃĢŢѷ 02+.JĚ͏Ο̞5>0O16Qu`ÜƜ̣3ƃʸ#J(C AR Qmbwgt &5ˋ̝3Ǥ̊HK.J 5) Ě͏Ο̞ˋ̝π/J flutamide 6&KΤБD AR 3ͯŏ #JÓĉ/˕ȌÁϵ˹/J hydroxyflutamide 3ƇɄK(5* AR 3DZĠ3ͯŏ#J & /ɜϕ AR QmbwgtNğώ#=UwY҅ʙN AR Qmbwgt5 PaWQg[Wu0ϕƤ!j̆G9Y˱ͧΆɄźNȼ ͨ!( ĭŏ˹5Y AR 5̖ˀȌ_pt0DZͯŏ!,Y5͏Ọ́ Ǎ҇3GI H12 QbwgtсǪ32J0NјƩ/K7KHĭŏ˹DZĠ2 AR Q mbwgt0!.Ö̊#J0NʀǺ!( &5ͯʎhydroxyflutamide GIDDZĠ2 AR ͯ ŏΚG9 AR Qmbwgt˕ȌN̹# BA321 G9 BA341 5ğώ3Ȟġ!(Ґū 4ґ6) 図 3 DHT と AR の結合様式(上図:立体視図)、および AR の活性化と H12 の関係(下図) 図 4 カルボラン含有 AR アンタゴニストの創製 -19- SAR News No.27 (Oct. 2014) BA341 と AR の ド ッ キ ン グ シ ミ ュ レ ー シ ョ ン BA341 0 AR 5up[^eeHBA341 5eQyź Gln711 G9 Arg752 0ˀͧͯŏNdzȞ!.J0̹şK(Ґū 5ґ @(}u[eoź6 Thr877 G 9 Asn705 5ïюYwź0ˀͧͯŏNdzȞ!.IDHT 0 AR 5ͯŏʦǬ0>?őʦ5 ͯʎǽHK( 3DMH$DHT 0̕2I AR Qmbwgt0!.ʬΚ!(06ѭ Ǜ3ΧŘ˜YAR 5 H12 QbwgtсǪNńJ0Nƕ.J0ΎHK ( up[^5ͯʎHH12 5ʥȞQyф/J Met895Ґū 5, ]ґ5ʷź BA341 5Y̆3ȽС!.IY5Ǎ҇ H12 NQbwgtсǪHȹѝ!( 0Qmbwgt˕Ȍ3ͯ9,(0ΎHKJ ,@IBA341 5Y̆6gr Su҅ʙ5̖҇ˀȌ5ʹȴG9͏Ọ́Ǎ҇3GJQmbwgt˕Ȍ5̟̂5җ,5 ǸĞN˨".J0ɨH02+( 図 5 B A 3 4 1 と A R の ド ッ キ ン グ シ ミ ュ レ ー シ ョ ン ( 立 体 視 図 ) BA341 誘 導 体 の AR ア ン タ ゴ ニ ス ト 活 性 AR Qmbwgt˕Ȍ5̟̂36AR 5 H12 QbwgtсǪNʹȴ/22JG2 ZuʥЩчϒ/J0HH12 Сñ3ÐΆ#J BA341 5}u[eoźпÐ5 ʥЩäѿNϦA( @(AR 5 Asn705 G9 Thr877 05ˀͧͯŏNΎȚ3āKˀͧͯŏȌ ƣΚźNɻ#J 1a-1h NŏȞ!ΆɄź5ǷѰ3,.ʠϠ!(Ґψ 1ґ ˀфźNɻ#JϬƸÓ 1a-1d 6BA341 GIίǝ AR <5ͯŏ6Ñ!(D55҇ͯŏΚN̹!( ɝ_tϬ ƸÓ 1f1g G9V[eϬƸÓ 1h /6 AR 3Ƴ#JͯŏΚ6Ѹκ3Ñ!( 5ͯʎ6 BA341 5}u[eoź5пĐ3ˀͧͯŏuv5Ɯůчϒ/J0N̹!.I up[^eeH°ˣK(̪³Ö̊ҐAsn705 5Ywź05ˀͧͯŏґ 0DΦ#J AR 5Дċ˕ȌĭϦ҃/6}u[eϬƸÓG9YwϬƸÓ$K3 .DƸā!(ΆɄźƋ2J0˕Ȍ5ÑϔHK(Ґ}u[eϬƸÓқBA341 > 1a > 1b2 ΆɄ}u[eϬƸÓқ1c > 1dYwϬƸÓқ1e > 1f > 1gґ @(Qs}u ϬƸÓ 1e BA341 0>?ő"5 AR ͯŏΚG9 AR Qmbwgt˕ȌN̹!(̄ ̌6ɨ̷/62Y5ѪƚŕǭȌ3GI˕Ȍĭ!(Ywźˀś!.J 021ΎHKJ BA341 5eQyź6ˀͧͯŏQ]im0!. Arg752 0 Gln711 0̪ ³Ö̊#J &/ĭŏ˹ 1c 5eQyźNGISgƁźȌ5҇Qioź<ƇɄ!(0 LAR 3Ƴ#JͯŏΚ6ʹȴ!(D55Дċ˕ȌĭΚ6Ѹκ3Ñ!( ˀͧͯŏ5ɝœ5 ƇĭEQioź5oпĐ3GJ͏ÓѣƩ21ĭŏ˹0 AR 5ͯŏʦǬĂÓ3ǷѰN¡ .J0ΎHKJ -20- SAR News No.27 (Oct. 2014) 表 1 BA341 誘導体の AR 結合能および転写活性化能 a Tris ͻχ˛3 hAR-LBD[3H]-DHTϦ҃ĭŏ˹NĢ4 oC / 15 ɮѓS[e!( &5ǻDCC /Ď ̄!дȃĐѧ!(˞3Ŕ@KJ AR ͯŏ[3H]-DHT 5ɍƶ˕ȌNˣƤ!( Binding affinity 6DHT 5 AR-LBD <5ͯ ŏN 100 0!(ɮ5̪Ƴͯŏ̀0!.͘ďK( b NIH3T3 ͪΘ3 hAR ̟̂gu0 AR Ȉ͗сēNŔB Luciferase ̟̂guNͭAОADHT G9Ϧ҃ĭŏ ˹NĢ5% CO2 Ɯů37 oC / 24 ɮѓS[e!( &5ǻeUj˕ȌNˣƤ!AR 5˕ Ȍĭ̀0!.Ʉ͘!( ǽHK(˭ǩÜƜɶH IC50 N͘ď!( Дċ˕ȌĭϦ҃/6Ϧ҃ĭŏ˹ AR <ͯŏ! (ǻH12 5сǪƇĭN½!( AR 5˕ȌĭјƩ5͆ǩłɪKJ(CAR binding affinity 0̪є!2ŽŏDJ AR フ ル ア ン タ ゴ ニ ス ト の 設 計 と 創 製 Flutamide 5яʀȩ¡3GJĚ͏Ο̞ˋ̝/6flutamide 3GIĚ͏Ο̞ƃʸȑĭ#J Androgen Withdrawal SyndromeҐAWSґN̛̟#J0̳HK.IAR 5 Thr877 Ala 3 Ƈ̕!( mutant 5̷̟̂ϪK.J 7) Flutamide E hydroxyflutamide 6T877A Ƈ̕ AR 36ͯŏ#JD55 Thr877 05ˀͧͯŏdzȞ/2(C&5Сñ3ÐΆ#J H12 ƫɩ 3QbwgtсǪ32I AR N˕Ȍĭ! AWS NǭЉ#0ΎHK.J ̂ůAWS 3 6Ƈ̕ AR 3DQmbwgt˕ȌN̹# bicalutamide Ǥ̊HK.JҐψ 2ґ8) BA341 6DZĠ2 AR ͯŏΚN̹!AR ÜƜ̣3ƃʸ#J SC-3 ͪΘ5ƃʸNʢC.Ñ˭ǩ/ȨĘ#J 0HĚ͏Ο̞ˋ̝5èύĭŏ˹0!.ʀǺK(ʷȉ203 BA341 D flutamide 0ő ʦT877A Ƈ̕ AR N̟̂!.J LNCaP ͪΘ5ƃʸNàЫ!( BA341 5}u[eo ź6 Thr877 0ˀͧͯŏNdzȞ!.IAla <Ƈ̕!( AR /6ˀͧͯŏdzȞ/$H12 ÀС/5ĭŏ˹5ͯŏʦǬƋƇĭ! LNCaP ͪΘ3Ƴ!.QbwgtÖ̊N̹!(0Ύ HKJ Bicalutamide 6flutamide ʦ5ʥЩ3яïюʥЩƸāK.IThr877 05ˀͧ ͯŏdzȞK2.D5пĐ H12 3̩Ƚ̣3͏Ół̟ND(H!.J &/BA341 5}u[eoźŗМ3͏Ọ́3Ǎ҇ïюNƸā#J00!( ĚУ!(G35 пÐŗМ/6oź5G2ΆɄźϣƫKJ0HoN½!.UwïюN Ƹā!(ĭŏ˹ 3a-3d4a-4d5a-5b NŏȞ!(Ґψ 2ґ -21- SAR News No.27 (Oct. 2014) 表 2 p-カルボラン含有 AR フルアンタゴニストの生物活性 Y0!. O E S Nɻ#JϬƸÓ 3a-3d G9 4a-4d 6bicalutamide GIÑ AR ͯŏ ΚN̹!(QitQuźNɻ#J 3d G9 4d 3DZ AR ͯŏΚϔHK( !!2 HƇ̕ AR ʖ LNCaP 3Ƴ#JƃʸȨĘ˕Ȍ63a-3c G9 4a-4b 5ɝ bicalutamide E 3d 4d GIDDZĠ/+( KH5ͯʎ6ŏȞ!(ĭŏ˹0 bicalutamide 5YпÐ̕2 J0EAR wildtype T877A mutant 5в3Љŧ#J0ΎHKJ ͳ.bicalutamide 0ő" SO2 YNɻ#Jĭŏ˹ 5a G9 5b 5˕ȌNϥÝ!(0Lbicalutamide GID Ñ AR ͯŏΚN̹!( ˺3QitQuźNɻ#J 5b 5 AR ͯŏΚ6Ѹκ3Ñ!( H3ΧŘ˜035a G9 5b ą3 LNCaP ͪΘ3Ƴ#JƃʸȨĘĥʎ6ϔHK2+( YŔɻĭŏ˹/6Y̆5̖҇ˀȌ̪³Ö̊ö(C bicalutamide 06̕ 2JʦǬ/ AR 3ͯŏ!.J0°ȓKĂÓ0!. bicalutamide 0Ƌ̕2JʥЩ˕ Ȍ̪є3Υ+(0ΎHKJ カ ル ボ ラ ン の 新 た な 利 用 法 を 目 的 と し た 非 bicalutamide 型 AR フ ル ア ン タ ゴ ニ ス ト の 設 計 ɹС/6 bicalutamide 3DȮȪȌN̹# Bicalutamide Withdrawal SyndromeҐBWSґ5żŖD KƖCЧǛ5Ě͏Ο̞)/2 AWS E BWS 3Dɻĥ2ȪQu`5ђ̟ɤȋ3˂ CHK.J 9) ĭŏ˹ 3b G9 4b 6bicalutamide 5ʥЩNź3sdS!.I bicalutamide 0Î(G2ĥʎN̹#0ΎHKJBWS 5Ľŧ02J AR 5 Trp741 5Ƈ̕3Ƴ!Y ̆ȤʬΚ#K7 BWS 3Dɻĥ/L $K3%GAR 5QyфƇ̕Nʿ3 !2HQmbwgtNğώ!ͳJ56Smo+ő˴/J &/ȟ6H12 QbwgtWNńH2G͏Ọ́3Ǎ҇Y/ H12 G9&5ŗМN̩ -22- SAR News No.27 (Oct. 2014) ȽјƩ#JG2ĭŏ˹NΎʚ!( #2M*AR 0 BA341 5eQyź5ˀͧͯŏN^i ʥЩ/ʨê#J03GIPaWQ/JUwYʥЩGI H12 3ȽС!(ɜ(2mS5 AR Qmbwgtğώ/J0ʀǺ!(Ґū 6ґ10) @( ^iź36ˀͧͯŏňΚ2пÐǢ,Ɯů#J(CeQyźNɻ#Jĭŏ˹GI DDZ AR 3ͯŏ#J0ΎHKJ /6^iϬƸÓ3Ƴ!.ǽHK(ͯʎ5 пNͫ½#J ŏȞ!(^iϬƸÓ 6a-6c 6$KD AR 3ͯŏ!(fXʥЩ NQit/âϸ!(ϬƸÓ 6d 6 AR 3ͯŏ!2+(Ґψ 3ґ K6ĭŏ˹5^i ź AR 5Qyфʷź0̪³Ö̊!.JϤȱ/Iʃĭŏ˹sdS5ƔDzȌNɋȴ# JʢC.чϒ2ͯʎ/J T877A Ƈ̕ AR N̟̂!.J LNCaP ͪΘ3Ƴ#JƃʸȨĘΚ6 Y3ΆɄź52 6c /Dǰ2HϪCHK( @(&5˕Ȍ5DZ6Y ̆HďJïю5я3ÜƜ!Ґ6a > 6b > 6cґ6a 6 bicalutamide 0>?ő͕5˕ȌN̹!( ʃͯʎ6Y̆ H12 N̩Ƚ̣3јƩ!.J0N̹ş!.J KH5ĭŏ˹ 6 bicalutamide 0Ƌ̕2JʥЩNɻ!.I BWS 3Ƴ!.Dɻĥ0ΎHK¼ǻ5ϥÝ ͯʎ3ʀǺ!( AR Qmbwgt3GJĚ͏Ο̞ˋ̝/6͖ͭ΄/5 AR 5Ö̊ȨĘKJ03GJ ͖щ5ÑŢѷ02J0DJ Ȫ AR π5ĜÖ̊5Еˡ36ȪQu`Ö̊0Ȫm |]őĭÖ̊5Đѧ ňʭ/Iͭ΄зỌ̃̄Qu`ŅƫÓĘǾπҐSARMґD@( ̦O3̶͋2K.J Ϩͪ6У=2ȟ6YNĖ̊!( SARM 5ȼͨD Ьυ!.IAR |eQbwgt215ğώ3DȞġ!.J 図 6 BA341 およびグリセロール誘導体 6a と AR の結合予想図 表 3 グリセロール誘導体の生物活性 -23- SAR News No.27 (Oct. 2014) おわりに ʃ͉/6ɜϕ̖ˀȌPaWQ3̨̰!(ğπ̶͋5¥5AR Qmbwgt5ğ ώ3,.ͫ½!( ɹС/6¤υ!.ЫC.JY5˹̄ĭƞ̶̣͋Hɜ(2˺ ȁN̟ϔ!ÀĢÝëNȴ(%(Ʀ̣̊2ıπèύĭŏ˹5ğώ<0̶͋ĉƫNͅ!.J ð ˴ȌƋ2ϒͧ/+(ğπ0Đш36̓ƞ5Ыʳ3GIϲ̣̄ϒͧĢM+(ʂ )3ͲƳ̣2ıπŜђ̟5Ȥˏ62 K3,.6̂ů5ğπȤˏ5ƉʦĭNϔK7ͥǽ /J/L Structure-Based Drug DesignҐSBDDґFragment-Based Drug DesignҐFBDDґ Computer-Assisted Drug DesignҐCADDґ21Ɖɔ5ȤˏɂŠK.J̵̧5ɝˏNз; 56ʢC.Ѩ! ɹɜ5ğπȤˏDΪŇHĖ̊K.JD5N̕2+(ϖ˲H ϔ̩#0Dчϒ/62)L ĿΎɗ˽ 1) Soloway, A. 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Design, synthesis, biological evaluations, and docking study of glycerol and aminoglycerol derivatives containing a p-carborane cage as novel androgen receptor full antagonists. To be submitted. -24- SAR News No.27 (Oct. 2014) ///// Activities ///// ʥ Щ ˕ Ȍ W 2014 ђ ô ż Ŗ ũѨĭ#JıπŜђ̟5̂˻0Ʒʉ ʥЩ˕ȌW 2014 ƦυƗŞя ҇ʁб ʥЩ˕ȌW 2014 66 ɺ 27 ɡ(ъ)ƋїƋƞaeim3. ũѨĭ #JıπŜђ̟5̂˻0Ʒʉ0ѷ!.ђôK( ɜϕıπŜ5ђ̟6ǟNФʻ3ũѨ32+..J ђ̟5ʽЖ̣ƫɩ2ıπŜ6ɠ3 ǔK..ђ̟3Dz(+.ÔH5Ƅ3;,JıπŜʷK.5/JHμ !Dz˴/6J !!5ƄN«IЋ2K7ɡʃ̟5ɜϕıπŜ5ђ̟6ϗʇ2 ˺3Сǟ/6QYsQ/ź̸̶͋Nυ&5ź̧ȧφNώπÇʡȈ̊#J0ūǬ 6Dz.6@H22+..J QYsQğπN϶&5ѓώπÇʡ6҇ǩ3̟б !(ź̧ȧφNђ̟!.J D*LOQYsQğπEώπÇʡ3Jź̸̶͋Ǣ, 5ȞʎND(H!.J06ІЅKJ=)0ȊMKJ5̂˻ɹж/J06ƺ 20DɗЁΏҐ҇ʁґ6Ύ.2 Ù7QYsQğπNυ36҇ƚý̈5ϝ MKJʶ5ϹNÿɽ#JȄϒI&5ÓĘQYsQ3ɕ+.J06ėǧȊ2 QYsQNŔBıπŜ̉ʡΤÓDȧφ̣̻Ẹ́3ʥЩ̣ƇĭNЉ!.I¼́( *6mw^St3͏+.J5D̳K2 ʃW/6ώπÇʡQYsQ0ϝ+(ʏͭA3Dz.6@H2ʦ2Ç̐Eͭ΄ 3GJıπŜђ̟5Iɝ213є!͒5ϴǘ5ý̈ɝHϧNÍ&5ǻ¼ǻ5 ɡʃ5ıπŜђ̟5Iɝ3є!.яɮѓ5|xsRgYpeNυ+( Dzɡ5^ 6Â5G/J ^ ҖҕQYs̟ğπƦ̂5(C5ɋɆxpt]5ńIͭA ҇ƚ ȂҐ˼͏υɎˏ» ıπź̶̧͋ȣґ җҕѻAHK2˷ǙȖʑ̛ҐNTDsґ̶͋<5ńIͭA ɜΉ б ҐQgrgώπʖǬÉ̻ґ ҘҕUnstructured/Structured Interaction Nʧ̣3!(ğπ ƹЏ ǮυҐPRISM BioLab ʖǬÉ̻ґ ҙҕFINDSҟrĄĩųıπŜ̶͋eh̟Ⱥ5ϦA ʋʃ ǯ̈ҐƁшΊώπʖǬÉ̻ґ Қҕ|xsRgYpe ıπź̶̧͋ȣ5҇ƚȂý̈36ɡʃ5QYsQ5ȴ,ź̸̶͋ĠNğπ3ͯ9,J= ƖCHK(ğπɋɆxpt]3,.˺3ıπź̶̧͋ȣ3ϢΆK(ğπɋɆȠ ̓Ƨ3Jğπv~0ğπQYS5²,5±ʡNϨ!ϛϯ!.ѱ( ğπ ź̧ȧφ0ˋ҃05ѓ3ʩ(MJʶ5Ϲ3ʫNʐJ±ʡ0!.¼ǻȄ$чϒ2ȞʎN D(H#/L06̗Õű620ȊMKJ QgrgώπʖǬÉ̻5ɜΉбý̈36§0!.̟ǁЦŭ5ÑȣǽΏǃN¥ȃ3νǫ !.JewQ̛eZg̚QY̱̮̚0+(ѻAHK2˷ǙȖ ʑ̛ҐNTDsґ3Ƴ#J̉ƣƞ̶͋ʬєҒŭѢ NPO 3GJͭ΄̣ńIͭA3,.ϛϯ!. ѱ( ɮ(Dŭĉ/6˷ǙȖʑ̛0!ȊMK.2+(s^˷˖υ5ü!Nϔ %D6E”uncontrollable”2˻ȗ32I,,IŭѢ̣36Vďτ˷Žŏ3G+. 6ŭ5Ɯ¶3єMJ˖υNϔ%.J ˷ǙȖʑ̛́(*3єMI52̙Ȑ/62 0NĊϪϷ%HK.ĴůѭǛ3mS2ϧѷ/+(0Ȋ -25- SAR News No.27 (Oct. 2014) PRISM BioLab ʖǬÉ̻5ƹЏǮυý̈36̂ů@/>0O1ȞġÙ52ͪΘĉς̡Їѓ ̪³Ö̊˺3 Structured-Unstructured ̪³Ö̊NĘǾ#J03GIıπŜђ̟3Jȧ ˏ3,.ϛϯ!.ѱ( ŭĉ/6ƺɔ5{SXoÇʡ/Iʶ5Ϲ3ʐ Jʫ0!.ʀǺKJEɠ3чϒ2ȞʎN,,J¼ǻ5ıπŜђ̟3ʭ%2 Ɯů/J06ϲNǺ(2 ˺3ʹĭ!(ΔΡ215ͭ΄5Νʹĭ0ˋ̝ˏ 21ƺ20DɗЁΏ6ňΚ/L0DΎ2+()3ȔŘ/҄̕5ȉNȴ+. Í0/( ƁшΊώπʖǬÉ̻5ʋʃǯ̈ý̈36ƁшΊώπN¥ȃ0!(XSye5 ϦA5,/JFINDSҟrĄĩųıπŜ̶͋eh̟Ⱥҟ3,.Ąĩ3GIQY sQ5ğπ3Jź̸̶͋N̟Ⱥ!ΣǥϦ҃<JϦA3,.Ϩ!ϛϯ!.ѱ ( 5fU]t6̂ů/6ŭѢĭЫASHIONOGI Science Program 0!.̂ů 11 Yŭ/ƦɞK.J050/J ıπŜђ̟6»ѺĂÓąɻ#=ϰѷ/I&5Ȟ ʎ6»ѺĂÓ¸Ņ#J=/L 5ǻϴ˨ѱ(ý̈ɝ3ʷ+.ѱ(|xsRgYpeɻȔΊ/+(0N ϡ!.472H2Ϩͪ6̫̓%.ѱ˳̺Nϣ!ѱ( ɹǻ32I@!(Ɖȇ2¥Ђч2ϧNΑ%ѱ( 4 Œ5ý̈ɝ35ŽNé IΦ!@!.˜Ȗϵ̎!@# @(ì&20Nɸ.@#5W 6ƦυƗŞ5˞ˀΪý̈Ґ̋МθώπʖǬÉ̻ґНαʪý̈ҐƁшΊώπʖǬÉ̻ґˁ ̋ƻý̈Ґ̶̓ώπʖǬÉ̻ґ¤93Qu{Sd5¦ɼƚý̈ҐɡʃɜπʖǬÉ̻ґ5 Ġ˳!36ђô/2+(D50ȊMK@# ƦυƗŞĂŞƦυƗŞя/JG2ƦυƗ ŞÉ/!( ƦυƗŞQu{Sd5 4 Œ5ý̈ɝ3ɌC.̺̎!@# @(ÉϟĎ ̄21҇ʁΰȤ2¾±NȤ3ǭŅ.K(56Dz̶͋Ƨ5Ǐ̄ɡ»ģɐ/# 5ŽNéI@!.ȖϵΦ!@# ƋїǨ06ϝ2H@I·Ч5ÞΪ2ÉŽ/+((CĿĢΏ»ɔȝȉK @!(ϟ 66 ŒD5ĿĢΏ3ʉŽĿĢϠϲNѱ@!( ĿĢΏ5̤ʦɝ+.5W )0Ȋ@# ЭK7%2H˜ϵ̎!@# ʉǟǩ5ʥЩ˕ȌW 2015 6ƯƋ2JļȔNѱ¥ƈώπʖǬÉ̻5Ƌ̋ѥ˵ ý̈3ƦυƗŞяNǭŅѱ@!( 2015 ǟ 6 ɺ 12 ɡ(ъ)3ɡʃπƞÉҀяµϡȉ 3.υMK@# ğπ3Jʦ2uğώȤʹ0&K3єMJ in silico ȧφ3є! .ϴ˨υMKJ°Ƥ/# ɭѭƉ5̤ʦ5ĿĢNѹ̎!@# -26- SAR News No.27 (Oct. 2014) ///// Activities ///// ҜÉŖҝ ͒ 42 Ŧ ʥ Щ ˕ Ȍ ̪ є e f T ɡɮқǞȞ 26 ǟ 11 ɺ 13 ɡҐʁґ14 ɡҐъґ ÉŽқ@D0ʞрȃdҐ860-0047 ˶ʃ̬˶ʃǔϑİɫɡ 1-14-1ґ §ôқɡʃπƞÉʥЩ˕Ȍ̪єпÉ ǻɆқɡʃĭƞÉғɡʃЛήĭƞÉғɡʃĐʌĭƞÉғɡʃЛπƞÉғɻʬŏȞĭƞĶÉ ͒ 1 ɡ ̨ Ґ 11 ɺ 13 ɡ ґ 10:00 - 10:05 ђÉ 10:05 - 11:05 Ω ϴ ˨ Ґ É Ž қ d ґ Ǫя қ ƨʃ̀ KO01 Prediction of three-dimensional structures and structural flexibilities of wild-type and mutant CYP1A2 by molecular dynamics simulations ĐƚħĠƞeeN̊(ш̈ųƇ̕ų CYP1A2 5͏ÓʥЩG9ʥЩ ʒГȌ5°ˣ Ґ1 ъˉƋќıπâғ2 ʊĮƋќπғ3 ĮцƋπғ4 їƋς̶̡ґˢлŁц˄ 1ғ ̿Őä 1ғÈρѥ 2ғǞſ̭Ǯ 2ғDŽ¬ɐ© 3ғǤшä 3ғƹ̋ǶŊ 1, 4 KO02 Non-empirical analysis of metabolic reactions of thioridazine by Cytochrome P450 2D6 Đƚ̓ƞϟ͘N̊(oXnf5 CYP2D6 3GJÁϵЯ͆5ѭ̣ͮ҃ϛʌҐIґ ҐȀljƋќπґ͓Ľÿęғ҂ljǵғŐ̋бϼғ¥҂Ư KO03 Development of in silico prediction model on environmental fate of chemical substances ̆Ƃ¥3Jĭƞ˹Ї5ĢˀĐϛȌ°ˣegr5ʥ͚ Ґ1 їƋќπғ2 їƋǿ̈˹̶͋̚ȣґƟʘ̅ 1ғdžʃɯĈ 1ғƨNjƋЂ 1ғ Ǐ̄ɡ» 1, 2ғ҇ʁб 1, 2 11:15 - 12:05 KI01 Ȱ Ǻ ϴ ˨ Ґ É Ž қ d ґ Ǫя қ ˁ̋ƻ Three-dimensional protein structure and dynamics in living cells ̈(ͪΘĉ/5ς̡Ї5͏ÓʥЩ0nSv]g ҐҁрƋƞʊ¹ ̄ǐƞ̶͋̓ґ˅ϹьĆ 13:30 - 14:30 KO04 Ω ϴ ˨ Ґ É Ž қ d ґ Ǫя қ҇ʁб Structure-activity relationship of ecdysone agonists bearing imidazole skeleton Snl͠Ν̥Qbwgt5ʥЩ˕Ȍ̪є Ґ¹ƋќЛґʩµƋ˓ғķˈ͡ғ̵ſijеғ¥ǏƓ͂ғƨǏȎ KO05 3D-QSAR study of neonicotinoid insecticides having a substituent on the 5 position of the imidazolidine ring Snlf̆ 5 Ð3͇5ΆɄźNɻ#JSn]uѺͽÓ5ŏȞ0ʥЩ ˕Ȍ̪єϛʌ Ґ1 ȕƙƋЛғ2 ¹ƋќЛґϑΜƴ 1ғяdž8J 1ғЈʋΉ͡ 2ғDŽĉΒ 1ғ ҁρΊĹ 1 -27- SAR News No.27 (Oct. 2014) KO06 Preclinical evaluation of COPD by means of hyperpolarized 129Xe MRI Њíʢ Xe MRI 3GJșȌёƀȌΖ̙ȐҐCOPDґ5ĚΣǥϥÝ Ґ1 їƋќıғ2 ¹ƋќȒżґʁʆɒ 1ғDŽĉͩЉƚ 1ғƑʆȘƍн 1ғ¼µƢǴ 2ғ ρĽαɨ 1 14:40 - 16:40 gmipe ҐÉŽқSVґ 14:40 - 15:40 Əɔ̟̔ψ 15:40 - 16:40 ðɔ̟̔ψ 17:00 - 18:00 KS01 ˺ ĕ ϴ ˨ Ґ É Ž қ d ґ Ǫя қ ¼µЙƚ How to predict the diversity of drug-induced liver injury? π˹ȌΔѣƩ5ƉʦȌ<5ƳȈ0°ˣ ҐŒŇǀƋƞƋƞќıƞ̶͋̓͠ґʩµʺ 18:30 – ȜϘÉ ҐÉŽқrwXmw˶ʃґ -28- SAR News No.27 (Oct. 2014) g m i p e [11 ɺ 13 ɡ KP01 Synthesis and 14:40 – 16:40] Ґ É Ž қ S V ґ structure-activity relationship of 8-hydroxy-2-imino-2H-chromene-3- carboxamide derivatives as CBR1 inhibitors 8-Hydroxy-2-imino-2H-chromene-3-carboxamide ҅ ʙ N ɻ # J Y w к ú у ͧ ҐCBR1ґјƩě5ʥЩ˕Ȍ̪є Ґ1 DžіπƋғ2 ƮDŽƋғ3 DžіƋғ4 ɬśƋґƨŶζʂǖ 1ғΙƋS 2ғдρɴŊ 1ғ γµόЂ 1ғʋˁá© 1ғ´IJцǶ 1ғʛ̋Ǝ 3ғĽɨ 3ғŏ̋˙ɨ 4ғϺdžƻʪ 2 KP02 Discovery of thienopyrimidinone derivatives as a new series of potent phosphodiesterase 7 inhibitors DZĠ2 PDE7 јƩ˕ȌNɻ#JɜϕoVyfyϬƸÓ5ğώ Ґ̶̓ώπґдρĦ½ғˊŏîƍнғ˗шʲōғƌш¢ˋғ˫̋ŰИғƼ͡ƚғ ҇ʫÌɨғŮ̋џғ¯µ˦ªғˁ̋ƻ KP03 Analysis of inter-molecular interaction between kinase domains required for transphosphorylation of receptor tyrosine kinase јƩěΐȌƇ̕Óoe[vj0јƩě05̪³Ö̊5ϛʌ Ґ1 ˶ʃƋπғ2 Į˚аƋғ3 SVƋƞґ¡Ǫ҉ɚ 1ғƹʫǏɓĹ 1ғʞdžǮȆ 1ғ ƌшÌˋн 2ғʩǏ̭ʜƚ 2ғJoseph Schressinger3ғ͈ŴčǴ 2 KP04 Identification of ligands of DJ-1 with biophysical screening ˹̄ĭƞ̣ȤˏN̊( DJ-1 ƹĐƚĭŏ˹g]w^ Ґ1 ʊƋќɜѴŷğȞ̓ƞғ2 ʊƋќǐғ3 ʊƋı̶̓ґ̋Áɰ 1ғJose Caaveiro2ғ яѐ̵ɵ 2ғ˔ʃ˙Ǟ 2, 3 KP05 Conformation changes in substrate binding site and differences in substrate recognition derived by variation of an amino acid in monkey and human carboxylesterase 2 }tG9cY[eVgrj 2 уͧ5 1 QyфƇ̕3GJźЇͯŏп Ð5ʥЩƇĭ0źЇϪϷȌ5̪в Ґ1 ˶ʃƋπғ2 Qg~XPғ3 ̉ͷ̶ґµǏש 1, 2ғρĽɘ 1ғϑ˫е 1ғ Ƌ˘ηÁƚ 1ғǤǏЂʮ 3ғ¼µЙƚ 1 KP06 Fish toxicity prediction of chemicals using atomic fragment method: Global parameters and chemical group parameters Ľƚ^tˏN̊(ĭƞ˹Ї5ҊʼȌ°ˣқ˃̊|m0æĕ| m ҐϺʫȧ̓Ƌќǐґ˅ό²ғ҇ʫ̌ѥ KP07 Study on binding of sodium phenylbutyrate to human serum albumin UwтфvtT5τ˞Qͯŏ˺Ȍ3є#Jẓ̸́ʠϠ Ґ1 NJŶƋπғ2 NJŶƋќπґDŽNjţ© 1, 2ғʤ̋˒½ 2ғdžʃÚƚ 2ғ̋ņśɨ 1ғ ƨʃ̀ 1ғ˯Ƽщ 1, 2ғƹ̋đùʪ 1, 2 KP08 In silico drug design of selective inhibitor of SHIP2 as a novel therapeutic agent for diabetes ɜϕ͟ƽ̚ˋ̝π0!.5 SHIP2 зỌ̃̄јƩě5 in silico ğπ̶͋ Ґ1 ĮцƋπғ2 ɬśƋπґƹ˫ɜн 1ғŏ̋˙ɨ 2ғǤшä 1 KP09 Partial similarity analyses of ligand-binding sites on proteins m|]Ї¥5ZuͯŏпÐ5пĐѺÎȌϛʌ ҐĮцƋπґDŽ¬ɐ©ғǤшä -29- SAR News No.27 (Oct. 2014) KP10 Structural predictions for small proteins by using molecular dynamics simulations ĐƚħĠƞˏ3GJƹm|]Ї5͏ÓʥЩ5ȾƤ Ґ1 ъˉƋќıπâғ2 їƋς̶̡ґƹ̋ǶŊ 1, 2ғ̿Őä 1 KP11 Development of a ligand-based virtual screening method for preliminary compound selection (part 4): A new approach for fingerprint-based similarity search °ọ́ĭŏ˹зȬ5(C5Zug{og]w^Ȥˏ5ђ̟Ґ& 5 4ґқʥЩRZt5ɌΪ ҐĮцƋπґоō¨ȏғϑ͐έǴ KP12 The construction of a pairwise database of ChEMBL ligands with 3D superimposition and structural transformation application ChEMBL N̊( 3D ч4ŏM%smgʥ͚0ʥЩƇɄ<5Ȉ̊ Ґ̶̄ CLSTґʫʃțɨғǠ̲ғʃѓþЂ KP13 Comparative analysis of intermolecular interaction of influenza neuraminidase with sialic acid substrate and its analog inhibitors ϜƘłȈʬʥ3ź-(SVdySwnj0eQфϬƸÓ05̪ ³Ö̊ϛʌ ҐȀljƋќπґά̋Ѥ̠ғŐ̋бϼғ¥҂Ư KP14 LERE-QSAR analysis of papain and trypsin hydrolysis of a series of substituted phenyl hippurate esters ҂ƽфUwVgr5egrS0irQj5ĢˀĐϛłȈ5Đƚ̓ ƞϟ͘3GJϨͪϛʌҐIґ ҐȀljƋќπґåʫɧƋғ҂ljǵғŐ̋бϼғ¥҂Ư KP15 LERE-QSAR analysis on complexes of HIV-1 PR with a series of allophenyl norstatin inhibitors Đƚ̓ƞϟ͘N̊( HIV-1 protease 0QUwygmo҅ʙNȴ,ĭŏ˹ 05ϏŏÓ5͞ƭ̪³Ö̊ϛʌ ҐȀljƋќπґʍɓ¨ғшΜѬғŐ̋бϼғ¥҂Ư KP16 Use of expanded perception of protein-ligand interactions as a fingerptint Ϩͪ2ѭͯŏ̪³Ö̊ϪϷ5 Fingerprint 0!.5Ė̊ Ґ1 Q]igʖǬÉ̻ғ2BIOVIA corporateґ҈džѤō 1ғDan Berard2ғ Helen Kemmish2ғJurgen Koska2ғTien Luu2ғNoj Malcolm2ғKatalin Nadassy2ғJon Sutter2ғ Adrian Stevens2 KP17 A novel 3D-QSAR analysis using FMO method and PLS regression FMO ˏ0 PLS Ŧǚ3GJɜϕ QSAR ҐĮцƋπґŐ̋ɴŤғǤшä KP18 Fragment based drug discovery (FBDD) vs molecular evolution: Shared strategy for the induction of substrate/target selectivity Ґ1 esRZʖǬÉ̻ғ2 їƋ JST ERATO ΛЇ˕ȌʥЩfU]tғ3 їƋ ќ̄ғ4 їƋź̸̄ƞfU]t̶͋imґǔĽŃ 1ғS Roy ʁʆ 1ғ ʋdžβ 2-4ғʄDŽȞ 2, 3ғʋLJƋИ 2-4ғʆ̋аѤ 2-4 KP19 Analysis of barnase-barstar complex with interfacial mutations, based on 3D-RISM theory 3 ʮú RISM ̄ϲ3ź-({vj-{gmϏŏÓ5ͯŏΚϥÝ ҐĮцƋπґ˞̋˒ғnjȞΉғ͑̋-ȆҌ̭̌ƚ -30- SAR News No.27 (Oct. 2014) KP20 Protein active site comparison with SiteHopper: Phylogeny to polypharmacology Ґ1 XQSf|ʖǬÉ̻ғ2OpenEye Scientific Software Inc.ґÒρ̀υ 1ғ Gregory Warren2ғPaul Hawkins2ғJ Michael Word2ғTom Darden2ғRobert Tolbert2 KP21 Study of novel series P2X3 receptor antagonists: Structure-activity relationships of pyrrolinone derivatives using homology model ɜϕ P2X3 ŅƫÓQmbwgt5̶͋ -fsN̊(yϬƸ Ó5ʥЩ˕Ȍ̪єҐƁшΊώπҐʖґґʕĽƐƚғɥîƍнғ̽̋˒ǴғѼˁό©ғ¯DŽЂ©ғ ̍ə˙Ǡ KP22 Development of the protein-gene sequence motif analysis system based on the codon reduced representation au͢ψ̂3ź-m|]ЇҔиÊƚсēoϛʌegr5ђ̟ ҐϺʫȧ̓ƋќǐґDŽʃ˪źғĢρĹɨ KP23 Mechanism for producing structure and functional variation of short chain dehydrogenase/ reductase (SDR) family proteins Short chain dehydrogenase/ reductaseҐSDRґPς̡Ї5ƉʦȌ˾ǽʬʥ Ґ1Ґ˼ґЛʡ̈˹Є˥̶͋ȣ2Ґ˼ґЛʡ̆Ƃȧφ̶͋ȣґĚ̋Ή͡ 1ғ¥ãǮ 2 KP24 Computational study on the interaction of high affinity binding ligand, calystegineB2 with β-glucocerebrosidase β-glucocerebrosidase 3Ƴ#J҇ϘśȌZu calystegine B2 ѺͽÓ5ϟ͘ĭƞ̣̪³ Ö̊ϛʌ Ґ1 ĮцƋπғ2 ƮDŽƋ̚ќπґ¥Оˎ 1ғĢρɒ 2ғŐ̋ɴŤ 1ғDŽ¬ɐ© 1ғ Ѝ͏ÈǑѤ 2ғǤшä 1 KP25 Off-target search with large-scale virtual screening data generated by the K supercomputer project Ƌϕʨ{og]w^smNĖ̊!(Xm`ptȼͨ ҐQg~XPʖǬÉ̻ґŭʃºғdžʃɒ© KP26 Development of the structural feature analysis system for molecules based on the threedimensional neighborhood information ʮúСñȒż3ź-Đƚ5ʥЩ˺ȁϛʌegr5ђ̟ ҐϺʫȧ̓ƋќǐґÒЃĦŝғĢρĹɨ KP27 Relation between eigenvector of molecular matrix and atomic environment of molecule Đƚυē5Ŭɻ]t0Đƚĉƾȣ̆Ƃ5̪є ҐϺʫȧ̓Ƌќǐґʞº̭ғ҇ʫ̌ѥ KP28 Development of integrated drug database and analysis of rhabdomyolysis by ATC codes ıπŜͱŏsmg5ÖȞ0 ATC au3GJʩ͖ͤσϛ̛5ϛʌ ҐєϑƞќƋ̄ǐґƋʞ͡»ғŻǏωȆғdž̋Ɲ KP29 Development of substituent conversion database and searching system for medicinal chemists “CUES”: Convert it Unique and Elegant Substructure ğ π ĭ ƞ Ώ 5 ( C 5 ʥ Щ Ƈ Ʉ s m g CUES: Convert it Unique and Elegant Substructure 5ђ̟0Ȉ̊ Ґ1 Ǘ»Pғ2 ̶̄ґ˶˫ţƚ 1ғÒʁáƍ 1ғǠ̲ 2ғʃѓþЂ 2 -31- SAR News No.27 (Oct. 2014) ͒ 2 ɡ ̨ Ґ 11 ɺ 14 ɡ ґ 9:30 - 10:30 KO07 Ω ϴ ˨ Ґ É Ž қ d ґ Ǫя қ ʃѓþЂ Investigation of dispersion interaction on complex formation of ligand with protein: Quantitative assessment of binding interaction energy in the LERE-QSAR analysis ZuҔm|]Ї5ϏŏÓdzȞ3JĐɑĠ̪³Ö̊5ʠϠ: LERE-QSAR ϛʌ 3Jͯŏ̪³Ö̊Vx\Ѳ5Ƥщ̣ϥÝ ҐȀljƋќπґŐ̋бϼғʍɓ¨ғåʫɧƋғ҂ljǵғ͓Ľÿęғ¥҂Ư KO08 LERE-QSAR and LIE analyses of binding affinity of γ-lactam hydroxamic acid derivatives with tumor necrosis factor-alpha converting enzyme Ξ̜ƅʶŧƚαƇɄуͧ (TACE) 0γ-]m}u[cфϬƸÓ5 LIE ˏ3źϛʌғLERE-QSAR ϛʌ0ʠϤ ҐȀljƋќπґшΨғˮшͶмғLjùÖғŐ̋бϼғ¥҂Ư KO09 Novel protein structure alignment method based on the residue-residue interaction ʷźѓ̪³Ö̊3ź-ɜ(2m|]ЇʥЩQStˏ5ђ̟ ҐĮцƋπґƲǘ˿ϡғ͑̋ҔȆҌ̭̌ƚ 10:30 - 11:10 KR01 Ü Ѷ ϴ ˨ Ґ É Ž қ d ґ Ǫя қ džljÌ© Lead discovery of selective kinase inhibitors against a novel kinase target by the bayesian prediction models based on the KINOMEscan data KINOMEscan sm3ź-(SfQ°ˣegr3GJɜϕ[vjʧ̣3Ƴ #JзỌ̃̄[vjјƩě5ğώ Ґ¥ƈώπʖǬÉ̻ ̶͋ʃпґяϹǏ˞ғžϹɎǮғƋ̋ѥ˵ғƼá©ғ ¥ϑΊ»ғƋś̋˪ғɽпƎғƹшƻΉғʘʊɊ 11:20 - 12:10 KI02 Ȱ Ǻ ϴ ˨ Ґ É Ž қ d ґ Ǫя қ DŽČΊ Molecular docking simulations in the era of network pharmacology Ґ1ˇ;̓ƞȧφƋƞќƋƞғ2egr{SXf̶͋ʬʥғ3̶̄ґKun-Yi Hsin1ғ Samik Ghosh2, 3ғĮшƢɨ1-3 13:30 - 14:10 KO10 Ω ϴ ˨ Ґ É Ž қ d ґ Ǫя қ ¥ǏƓ͂ Analysis of pH-sensing mechanism for sweet taste-modifying proteins at acidic condition Řϗäѿm|]Ї5ф3GJ̇Ř̟̂ʬʥ5ϛʌ Ґ1 ɜ˩πƋȈ̈ғ2 ʊƋќЛґƋ¨âNJ© 1ғ¥ǎîɾ 2ғÈρţ̼ 2ғŲǒ 2ғ љпţƚ 2ғ̋ƨƦ 1ғ̵ҎʱЏ 1 KO11 Anti-inflammatory effect of self-assembling heparin derivatives and their structure-activity relationship ΤǓͭ΄ĭ|ϬƸÓ5Ȫ˰̛Ö̊0ʥЩ˕Ȍ̪є Ґ¹ƋќπґDŽƮΊғHasan Babazadaғʫ̋û 14:10 - 14:50 KO12 Ω ϴ ˨ Ґ É Ž қ d ґ Ǫя қЈʋΉ͡ Physicochemical characterization of the interaction between CapF and small molecule Staphylococcus aureus εΠŏȞуͧ CapF 0ÑĐƚĭŏ˹5˹̄ĭƞ̣2̪³Ö̊ϛʌ Ґ1 ʊƋќǐғ2 ʊƋ OCDDғ3 ʊƋќɜѴŷғ4 ʊƋı̶̓ґяѐ̵ɵ 1, 2ғ ¥ͥǤн 3ғƨȢƝþ 3ғCaaveiro Jose1ғ˔ʃ˙Ǟ 1-4 -32- SAR News No.27 (Oct. 2014) KO13 Analysis of inter-molecular interaction between kinase domains required for transphosphorylation of receptor tyrosine kinase oe[vj5фĭ3GJ˕Ȍĭ5ʥЩYwh Ґ1 ˶ʃƋќπғ2 Į˚аƋғ3 SVƋƞґƹʫǏɓĹ 1ғƌшÌˋн 2ғ ʩǏ̭ʜƚ 2ғʞdžǮȆ 1ғJoseph Schressinger3ғ͈ŴčǴ 2 15:00- 15:50 KI03 Ȱ Ǻ ϴ ˨ Ґ É Ž қ d ґ Ǫя қ Ƌ̋ѥ˵ Studies of enzymatic reaction mechanisms by X-ray crystallography X ͯɳʥЩϛʌ3GJуͧłȈʬʥ5ϛɨ Ґ˶ʃƋƞƋƞќ̈Ś̓ƞ̶͋пґDŽͿFIƚ 15:50- 15:55 ёÉ -33- SAR News No.27 (Oct. 2014) ʥЩ˕Ȍ̪єпÉ5ˌѯ0Ќɣ 1970ǟÁ5ĚĴıЛπNŔB̈̄˕Ȍ˹Ї5˕Ȍ̟̂5Đƚʬʥ͏ÓʥЩѪƚʥЩ5ϟ͘E˕Ȍ smĎ̄3Ƴ#Jam5˕̊21єЪĐш5C @!̟ǁ30D2+.ʥЩ˕Ȍ̪є0 ĐƚϢϟ3Ƴ#Jɜ!ɝˏϲ¢̣̑3ʼnѵ!.( 5G2ȒĪ3řȈ#J00D3̶͋Ώ5 ·˖0Ȓż·Ʉ̶̟͋ψ0ɝˏϲ5ɱŀ5ŽNɂÛ#J0Ṇ̨3Ϣ͏K(5ʃпÉ5ĚБ5ʥ Щ˕Ȍ̪єȜϧÉ/J 1975ǟ5ɺ¹р3.͒1Ŧ5ȜϧÉ(efT)ɟɃK1980 ǟH6ǟ1Ŧ5ʥЩ˕Ȍ̪єefTєßϳƞÉ5ąô5/Ƥʀ̣3ђôKJG32+ ( 1993ǟGIőefT6ɡʃπƞÉıπĭƞпÉ5§ô5єßƞÉ5ąôNǽ.υ2MKJ 002+( ʥЩ˕Ȍ̪єȜϧÉ61995ǟ3&5Œ̈́Nő̶͋É3ɌCefTђô5ƦĨȯDz^ 0!.5ǸĞNʎ#002+( 2002ǟ4ɺH6ɡʃπƞÉ5òͭ΄5ʥЩ˕Ȍ̪єпÉ0 !.Ċď̟!єЪϳƞÉ0ƭȽ2ЪɈNâ*,,̈̄˕Ȍ˹Ї5ʥЩ˕Ȍ̪є3є#Jƞφ̶͋5 ȷΧ0ȾЫ3œ.˕ħ!.J ̂ů&K'Kǟ1Ŧ5efT0WNђô#J00D3 пÉϩ5SAR NewsNǟ2Ŧ̟υ!єßѴŷ5ɹɜ5ȒĪ3є#Jţλ0Ǥż˕ħNυ+.J ʃпÉ5ˌѯ0ЌɣG9ɹɜ5ħœ215Ϩͪ3є!.6 fNĿ˵ѱ( (http://bukai.pharm.or.jp/bukai_kozo/index.html) ͺѦǻϡ ɡʃπƞÉʥЩ˕Ȍ̪єпÉϩ SAR News ͒ 27 ŌNƿ(!@# ¼Ō5 Perspective/Retrospective /6̄ĭƞ̶͋ȣ5ʃѓý̈3̶̄5ğπı̝ȧφź̧^5ͫ½0 FMO-PBSA ˏ3,.ϛ ϯ()@!( ͞ǩ҇Ãȓg]w^Eup^sdS5ȧφQYsQ̟ğπ/6ч ϒ2ź̧)0Ȋ@# FMO-PBSA ˏ8.6̉ʡ̑3ːŀ#JʀǺDǤI@# Cutting Edge /6 &5 FMO 5ɹɜȒżNɡʃƋƞ5̿˫ý̈3ͫ½()@!( FMO ͯɳʥЩHZu0 ʧ̣05ѓ5̪³Ö̊5ĭƞ̣ȌЇNϛʌ/J)/2SBDD 5ď̟ű˲/JϏŏÓʥЩ5͞ƭ ĭ3DȈ̊/J0˲Ļϻ̣/!( ʊĮπ̓Ƌƞ5ƍ̋ý̈36̃˻/҇͏Ój /JY҅ʙN˕̊!(̶͋Nͫ½()@!( ҇ĭŏ˹5ŏȞ6ũѨ/J 0Ɖ0Ȋ@# Y6ğπq0!.D¼ǻDʦ2Ȉ̊ʀǺK@# ʃǟǩ5ʥЩ ˕ȌW/6҇ʁпÉя5żŖ50IQYsQ̟ğπDчϒ2ϧѷ5,/!( ¼Ō 5ĉƫD&K3řȈ#JпĐI@# ʃпÉ5˕ħȟŭ5ğπ3¼ǻDϿ˽#JG3ĤC( 0Ȋ@# 2¼ŌHʃϩψͦ5bƇɷ32+.I@# b3ОCHK(ʃпÉ5ʵŊ0 Ȋ̄ȉD:C&5ͮͼ3,.҇ʫ̌Ѥý̈HƬ͉()@!( ɹǻ32I@!( 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