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SAR News	
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1.

はじめに

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2.

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SAR News No.27 (Oct. 2014)

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SAR News No.27 (Oct. 2014)

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SAR News No.27 (Oct. 2014)

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^Nυ+(ͯʎ ʊƋ5ğπXSyeim5S[8]HзȬ!(ĭŏ˹ RK-9024466  HCK 3Ƴ!. IC50: 7.7 nM 5јƩ˕ȌN̹!(Ґū 5ґHCK 0 RK-90244665ϏŏÓʥЩN̶̄5ʩǄH5^ϛʌ! &K3ź-(ϢϟNυ ʽЖ̣ПШ3
IC50: 0.43 nM Nȴ, RK-0020449 Nϔď#03Ȟġ!(RK-449 6 ̡τ̚ȐΏ̌ʉ5ǡͪΘE &5ǡͪΘNƃʸ%Ā̘ ĂTg3ͅʟ!(ħ˹s3.҇ĥʎN̹![9] ̂ů ΣǥϦ҃<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|ΞH̟ϔK( Ser/Thr kinase /I STAT |gTUS5˕Ȍĭ͕NЧ!.
̡τͪ̚Θ͕5ƃʸ0̈Ɯ3.чϒ2öN!.J ȋȌ҅҆Ȍ̡τ̚5ğπm`pt/J ɗп̓ƞ̫m`ptm|]̶͋^3. ̶̄5̋ÄH5^̟
ʚ! ʊƋяшH5^05ąő̶͋3G+.јƩě5Seag]w^0&5-7-

SAR News No.27 (Oct. 2014)ū 5. HCK ј Ʃ ě 5 S  e  a ğ πǻ5ϬƸĭǁђNυ+( &5Я͆3,.6 ͦѮ5рŏDIϨ!У=2 PALLAS
3G+.зȬ!(up[^ʈÅ3GJSeag]w^3G+. IC50: 400 nM ͆ǩ5јƩěN̟ϔ![10] &5ǻ5Ϣϟ0ŏȞ3G+. 1 nM ͆ǩ5јƩě@/ėб!.J[11]5 Pim1 5јƩěϢϟ3. ʥЩ5ƹ2Ƈĭ3G+.°ʀ!2Ƌ2˕ȌƇĭҐM
FJ activity cliffґNͮ҃!( ū 6 5Ǒï3ĭŏ˹5ʥЩ0˕ȌN̹# ŋ΍5 5-6 ΁̆͠5
1 æ5˱ͧ͎ͧ3ƇMJ03G+.ɹƋ/ 200 ç͆ǩ˕ȌÑ!.J 6 ĭŏ˹5*
4 ĭŏ˹6ϏŏÓ5 X ͹ʥЩϛK.J >0O1ʥЩ6ő"/I Ǽʉ5ĐƚĠŽ3
ź- MM-PBSA /6 log IC50 05 R2  0.59 0Ñ̪є!̹2+( &/ KH
5ϏŏÓʥЩҐŀ9 X ͹ʥЩ5˳ 2 ĭŏ˹5sʥЩґN QM-MM 3G+.Vx\ɹжĭϟ͘! FMO 5 IFIEҐ^tѓ̪³Ö̊Vx\ґ5ŏϟë0 MM-PBSA 5 PBSA
ѲпĐNŏM%(ëNϟ͘! log IC50 05̪єNϔ(0L R2=0.92 0҇̪єN̹!(Ґϲɗȩ͉˦ó¥ґʃ̶͋3.6 m|]ЇҔZuϏŏÓ5ʥЩ5ŜЇчϒ/+( X ͹ʥЩ&5
D5E ĐƚĠŽ/Vx\ɹжĭ!(ʥЩ/6 MM-PBSA /6Ͻ5̪є FMO-PBSA /D R2 / 0.3-0.5 ͆ǩ/I ¼Ŧ5G2ʥЩƇĭ5ƹ2ĭŏ˹ipt3J activity cliff
5°ˣ/6 ˺3ʥЩ5ŜЇчϒ/J0̹şK( !! @) 1 m`pt/5ͯ
ʎ/I smiptDƹ5/ ¼ǻ6Ϗɔ5̕2J͇Ѻ5m`pt/ 10 ĭŏ˹Â
5ipt/5ʠϤN΅IТ#°Ƥ/J @( PB (Poisson-Boltzmann)Ѳ3,.6 ǲ̶͋Ƨ
5ˢлH3G+. FMO 3G+.ϟ͘#JɝˏDђ̟˟A[12]/J 1 æ5ϟ͘ëNǽJ(C3 FMO ϟ͘NÔŦ΅I#ȄϒI ϟ͘ɮѓѭǛ3я 5пĐ5ĥ̀ĭ͕Dυ щƚĭƞϟ͘/ʥȞK( 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

QYsQğπ3JSeag]w^ Ϣϟ5ǸĞ6ѭǛ3Ƌ ƋȤώπÇ
ʡ5G3˹щ3G+.јƩě5ȼͨŏȞNυ0ũѨ/J(C Ñagt/Ƌ2chemical space Nȼͨ! ŏȞ#Jĭŏ˹NͰIОB06чϒ/J ́(*5̶͋Ƨ/6Ʀ̣̊2ȧφҐPALLAS, MUSES, LAILAPSґ5ђ̟00D3 ʮ¢Á5ɹý͐ȧφҐFMO-PBSAґ
5ђ̟3DńIͭO/J ˺3͞ǩ5҇ͯŏϘśȌ°ˣ/6 Ǽʉ5ŇĈĠŽ/ÖȞ!(sNѪƚƭǩ3жŏ%.ˆƤ#J X ͹ʥЩ/6 ĲĐ/J ̂ů ɡʃƋƞ5̿˫ ̽ȡƋƞ5̋¥H00D3ɹĔH FMO 3G+.ʥЩˆƤ#JȤˏҐFMO ЊĐϛΚʥЩˆƤˏґ
Nђ̟!.I V]c215ʮ¢ÁƋϕʨϟ͘ʬ0ЪɈ#K7 PDB 3̠эK.JĂm|]ЇʥЩ5ĊˆƤDƊ/62 ɡʃ̟5¢̑ʧ˦5ʥЩϛʌȤˏ3̟ǁ#J0NʀǺ!
.JϵКʃ͉5Ÿ͔3(I ĶĠ()@!(̶̄ DMP 5˜ϔ͑Ǥʦ â̭̋Łƚʦ ɡʃƋƞ5̿˫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).

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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 ʳɡʃƋƞʋȡʴƞп̿˫ ο

1. は じ め に1999 ǟ3Į˘śƎɐȸH3G+.ɂʚK(^tĐƚВаҐFMOґˏ[1-4]6 5 10ǟѓ/Ƌ̟ǁ! ̈Ó҇Đƚ͠5̪³Ö̊ϛʌq0!.Ƥ̰!,,J щƚĭƞϟ͘
3G+.m|]ЇEZuϏŏÓĂÓ5Ѫƚ˻ȗǽHKJ5ɝˏ6 ˺3ğπĐш3.6ɤH Structure-Based Drug DesignҐSBDDґ<5˕̊ʀǺK ώπÇʡ3GJĖ̊DЫO/J[5-8] FMO ˏ3є!.6 ɹС5ɡʃĭƞÉ5ȒżĭƞпÉϩ3Ŧ3ˢ+.˺
ѦK.J0HDˑ̨ǩJ[9]FMO ˏ6 m|]ЇNQyфʷźĸÐ215^t3ĐĞ! ŗМ5^tH5̆ƂѬѪre¥/^t5yҔEnS5Ѫƚ˻ȗNϛ Đƚ
ĂÓ5Ѫƚ˻ȗNĊʥ͚#JСÎȤˏ/J ¤ēĭĥ̀GЊ¤ēϟ͘ʬ3œ.I,˃̊ȌD҇ ÔGID҇Ш҇͞ǩ2ĂѪƚϟ͘Ȥˏ/J03̒@H$ Đƚѓ̪³Ö̊5ʣȉNАϐ!.J(Cĭƞ̣̩ϙ3ˌ+(ȒżǽHKJ5ɹƋ5ǱA/L FMO ˏ
5(C5ϟ͘^6ϏɔJ ʃ͉/6ȟ 5̶͋^/ђ̟¥[10]5 ABINIT-MP
3GJğπĐш<5ǁђ3,.ʣϯ#J FMO ˏ6̪³Ö̊5ϛʌ3.ʢC.ɻ̊2ɝ
ˏ/J ňϖĭϛʌʬΚNûƦ%J0/H3ɻ̊Ȍƃ#(C Ƶ̊ňϖĭ GUI /J BioStation Viewer 5ђ̟D͊ʢ̣3ЫC.J
2.

相 互 作 用 解 析 ツ ー ル と し て の FMO 法

FMO ˏ/6 ĐƚN ^t3ĐĞ#J0 &!. ^tѓ5̪³Ö̊Nϛʌ/J0Ƌ2˺ȁ/I &KH0@Àŏ0Ƌđ/J^t̪³Ö̊5źʃĸÐ25/ ˑ̨!(̪³Ö̊ǽHKJG2ĐĞN!.0/ǻ5ϛʌEIɩ2J ĐĞ3Ѣ!.͞ǩʠϤK.J56 sp3 ˱ͧN Bond Detached
AtomҐBDAґ0!(ĸͯŏ/5đɛ/J03ˑȔ! &KÂƈ5Žŏ36ʠϤ!.H5
Ė̊NīC#J ЧǛ6 m|]Ї6QyфĸÐ/ĐĞ! Zu5ÑĐƚĭŏ˹6Ă
ÓN 1 ,5^t0!.ψ̂#J0Ϊϟ͘͞ǩ5ͯʎǽHKJ ĭŏ˹5ĐĞEQyфïю5ĐĞ3,.6ƉÓ FMO ˏ[11, 12]̊HKJ
2.1 IFIE と PIEDA^tѓ5̪³Ö̊0!.ɹD͛Þ/Ϊ̊HKJ5 ^tѓ̪³Ö̊Vx\ҐInter-Fragment Interaction Energy; IFIE @(6 Pair-Interaction Energy; PIEґ/I 
KH6ĂVx\5͘ď0őɮ3ǽHKJ ŅƫÓҔZuϏŏÓ3Ƴ#J FMO ϟ͘6
IFIE NVx\ȵʧ0!.ZuҔʷźѓJ6ʷźőƆ5̪³Ö̊NƤщ̣3ϥÝ#J0/J(C ϲ̣̄2up^sdS3ж!.J Ù0!. ū 1 3ΖO5m
`pt/J EGFR oe[vj0јƩě erlotinibҐšŜŒmi{®ґ05ϏŏÓʥЩ
3Ƴ#J FMO2-MP2/6-31G*5ϟͯ͘ʎN̹# Ǒ5͏Óū/6 IFIE 5ë0͏ÓʥЩ5є
ßNΎư#J0/ ŋ5 IFIE map /6 ^t5ĂͭAŏM%3Ƴ!.ǽHK
J IFIE ëN͵Έ/J3 distance matrix 0ʽЖ#J0/҇ʮʥЩ0̪³Ö̊5єЪÀDňΚ/J ,@I X ͹ͯɳʥЩϛʌ͕3G+.ǽHKJ͏ÓʥЩH6ЎѧȒżɨH32
Iˀͧͯŏ215̪³Ö̊D°ȓ#J0/J &5ͯɳʥЩ3Ƴ!. FMO ϟ͘Nυ0/Ƥщ̣2̪³Ö̊ȒżNÀĢ#J0/J
H3 IFIE N 4 ,5Vx\ȞĐҐѬѪVx\; ES ·Ʉł̟Vx\; EX ѪδͅħVx\Ғ҇ʮѲ; CT+mix ĐɑVx\; DIґ3ĐĞ#Jɝˏ PIEDA ҐPair-Interaction-10-

SAR News No.27 (Oct. 2014)

Energy Decomposition AnalysisґĮ˘Fedorov H3G+.ɂʚK.J [13] Erlotinib 6̖ˀ̣2ƣΚźNƉŔA [vj0ˀͧͯŏ!.J56[vl̆5fпĐ)/IʃɔDƺ2 PIEDA ϛʌH ˀͧͯŏ3Ģ.Ѫδ5ͅħNË+( CH…O ˀͧͯŏE CH/̪³Ö̊3G+.̪³Ö̊ƠƤĭ!.J0ɨH32+( ˺3ĐɑĠN§ȞĐ0!.Zu0̪³Ö̊#JʷźƉɔƜů!.JҐū 1ґ
ū 1 EGFR oe[vj0 erlotinib 05̪³Ö̊ϛʌ Ǒ6 IFIE 5͏Óňϖĭū/I
ҍΫ/̹#Zu3Ƴ!.Ŏʷź5̪³Ö̊5ǱNЈѫΫ5˭/ψ!.J ŋ6 IFIE
map G9 distance matrix 6 PIEDA ϛʌ[14]3GJ ES EX CT+mix DI ŎȞĐ<5ĐĞN
ψ# Vx\5ĸÐ6 kcal/mol
2.2 多 体 FMO 法 と リ ガ ン ド 分 割
PIEDA 3GJVx\ȞĐ5ĐĞNυ0 ̪³Ö̊5ȌЇMJ(C SBDD 3GJϲ̣̄2ğπ3Ǹ͏, ɝ/ Ƌ2ĭŏ˹NǢ,5^t3ĐĞ! пĐʥЩ5̪³
Ö̊NϥÝ/J0Ǹ͏,0DJ ƣΚźĸÐ5̪³Ö̊NϥÝ#Jɝˏ0!.6 MFJ^tĭŏ˹ҐFragment-Based Drug Design 3J^tґ5G2ƣΚź͆ǩ5ƹĐƚ3Đ.!@ɝˏ0[6] Җ,5ĭŏ˹N FMO ˏ5^tĐĞĎ̄/Đ

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SAR News No.27 (Oct. 2014)

JɝˏJ[12] ǻΏ5Ù0!. SVdTSg5ySwnjҐNAґ0zanamivirҐšŜŒd®ґ5̪³Ö̊3.6 £ȌSX/JZuĂÓN@0C
JGI6ʬΚпÐ03^tĐĞ!(ɝ ŗŪ5Qyфʷź05̪³Ö̊Nжđ3
ϥÝ/J ū 2 6 zanamivir N 4 ,5пĐʥЩ(1)~(4)3ĐĞ!( FMO4-MP2 ϟͯ͘ʎ/JϽѪδNȴ,(1)0ʱѪδNȴ,(2)5^tŗМ5δѪȌQyфʷź0Х5ƠƤĭ̪³Ö̊N!.JʦƚE ¥Ȍ^t/J(3)(4)0ˀͧͯŏ#JŗМʷź05ѓ3ƾȣ̣2ƠƤ̪³Ö̊JʦƚNɔẹ̈3ϥÝ/J 5G2Ȓż6ƣΚź5sdS3ɻ̊/J Ï! GIͪ^t<5ĐĞ6ϟ͘͞ǩNι0#032JȍKJ 1,5ƳĎˏ65Ù5G3ƉÓύʱ FMO ϟ͘[11]N̊J0/ ĐĞ!(Zu5Ѫƚ˻ȗ5®KNύʱ! ĭŏ˹0!.5ȌЇNɇ202ϛʌ#J0/J[12] ZuͯŏcSt5 IFIE 3є!.6 sp3 ˱ͧ/5đɛNυ+.K7 ƋȮ6 FMO3 ύʱ/ĴƤщ̣2ëǽHKJ0̣ͮ҃3̷CHK.J

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2.3 相 互 作 用 解 析 の 流 れIFIE g5̪³Ö̊ϛʌ36 ¿3D VISCANA [15]215ĭŏ˹]gm^ȤˏD
J ABINIT-MP 36Ва/H3Ϩͪ2ϛʌN#JȤˏ 2 ,ƦϊK.J 1 ,6ˀͧͯŏ͕5Ѫδͅħ̪³Ö̊Nȥ0/J CAFI [16] D 1 ,6 CH/ πEπ/π215Đɑ̪³Ö̊Nȥ FILM[17]/J У5 PIEDA 5ŎȞĐ5* CT ѲN CAFI DI ѲN
FILM 3G+.GIϨͪ3ϛʌ#J0Sf32JҐϨͪ2ɝˏϲ3,.6ĿΎɗ˽N
Ŀ˵K( @( @/D̕2J^tѓ5Ва̪³Ö̊/J03ˑȔ#Jґ
K@/3ď.(ϛʌȤˏNͷŏ#J0 ū 3 3̹#G2ϛʌ5˖Kϔ.J @$6ЧǛ5 IFIE ϛʌ3G+.͵Έ̣2ϛʌNυ Zuͯŏ3чϒ2QyфN˺Ƥ#J
/^tĐĞ5͞ǩDoUp]#J Ȅϒ3Ȉ".ƉÓ FMO ϟ͘NńIāKJ PIEDA 3G+. IFIE 5Vx\ȞĐNĐϛ! ̪³Ö̊5ȌЇN̄ϛ#J ˺3 CT DI
ȞĐчϒ2ʷź3є!.6 CAFI E FILM ϛʌNυ ƣΚź5Ва15G2̪³Ö̊
N!.J5NɨH3#J #J0/ ͯŏ5чϒ2пĐ3WYg!.0/J ƻ Ă.5ig3.ȵʧ02JɔëǽHKJ-12-

SAR News No.27 (Oct. 2014)ū 3 FMO ˏ3GJ̪³Ö̊ϛʌ5˖K
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ZuŗМ3є!.6 G>1҇ĐϛΚ5 X ͹ͯɳʥЩϛʌNυM2ћI ĲĐ3ãѶ/
JʥЩNƦ̣҃3ǽJ06Ѩ! K@/5ȟ 5ʠϠ/D up[^ʥЩ3.ZuпĐ5ʥЩN QM ϟ͘/ˆC̩#0/ͯŏVx\ɔçDƇĭ!(I ͞ǩ Ĳ
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.6 ͞ǩ ĲĐ2ʥЩ6Ϯ+(ϛхN¡JȍKJ &/ɹС6 FMO ˏ3GJʥЩ
5͞ƭĭ3ĠNāK.J[18, 19]
3.1 構 造 最 適 化 の 重 要 性ʃŌ5 Perspective/RetrospectiveҐʃѓý̈ґ/Dͫ½K.JG3 QM ϟ͘3GJZ
uŗМ5ʥЩɹжĭĭŏ˹5˕ȌN°ˣ#J/ˆƤ̣32J0J ˺3 FMO ˏ3
GJVx\ϟ͘E̪³Ö̊ϛʌNυŽŏ36 ̊JʥЩ0 FMO ϟ͘5{gƋđ02J @( }gof5tĭ˻ȗ5ˆƤ3DʥЩɹжĭ6ɻ̊/J }gof6у͕ͧ5ʬΚ̟̂3ßJчϒ2ʷź/I &5tĭ˻ȗ6Ľƚ/5łȈYwh3ˆƤ̣2ǸĞNʎ(#(C m`pt15tĭ˻ȗ3J5N̳J06чϒ/J Vgt`ŅƫÓ5Zuͯŏ3J}gof5ˀͧÀĢ˻ȗNϥÝ!
(ÙNū 4 3̹#ҐZu6 17β-estradiolґ ¥Ȍ˻ȗҐHID HIEґG9tĭ˻ȗҐHIPґ
5 3 ʥЩ3,. FMO ʥЩɹжĭNυ+(0L HID /6Snl̆ͯɳʥЩ5Ѯ
H$K HIP /6ˀͧͯŏŅƫÓ5 Glu 5§ю5Ywź<5tͅħЉ+.
HID 32+.!@0Đ+( H3 HID 0 HIE 5ɹжĭʥЩ/6ˀͧͯŏ3JѪδͅħ5œ̕2I HID GID HIE 5ɝ ZuͯŏVx\ 10 kcal/mol ͆ǩƋ2J0M+( Ǽ+.Zuͯŏ3.6 HIE ˻ȗùÐ/J0ΎHKJ
ŧA3 ū¥5 CAFI 3GJѪδͅħ5Ва̪³Ö̊ϛʌ/6 Ɣǲ2Ɂ÷NǽJ(C36
QM 5ʥЩɹжĭȄϒ/+(-13-

SAR News No.27 (Oct. 2014)ū 4 FMO пĐʥЩɹжĭϟ͘3GJ}gofˀͧÀĢ˻ȗ5ϥÝҐқɹжĭʥЩ5ʽЖ қCAFI 3GJВа̪³Ö̊ϛʌґ
3.2 FMO 超 分 解 能 構 造 解 析
FMO ϟ͘3GJʥЩ͞ƭĭ5D 1 ,5Qo FMO ЊĐϛΚʥЩϛʌ/J FMOϟ͘Nυ(C36 ź32J X ͹ͯɳʥЩĖ̊/J0ĚɂʈÅ/I K@/6
RCSB Protein Data BankҐPDBґ/ĄђK.JʥЩNĖ̊!.Vx\ϟ͘EʥЩɹжĭ
Nυ+.( &K3Ƴ!. FMO ЊĐϛΚϛʌ06 X ͹ͯɳʥЩϛʌ5ig3̩Ƚ FMOϟ͘NĖ̊!.ѪƚƭǩȒż͕Nύơ! ʥЩˆƤ5͞ǩNœ%G0ȧφNȵ! ̂ů ̄ĭƞ̶͋ȣ5ʃѓ^E̽ȡƋƞ5̋¥^0ąő/̶͋NЫC.J ˺3
ZuŗМ5сǪˆƤ5҇͞ǩĭEaW5ĺɻ̀5͞ƭĭ ˀͧĽƚ5ÐΆˆƤ3є
!. X ͹ͯɳϛʌ5ĐϛΚ 2.0ҟ3.0 ͆ǩ5sm3Ƴ!.D ƦЇ̣3GI҇ĐϛΚ5Ʀ
҃smNǽJ50ő͕50бȞ/J0N̨ʧ3!.Jū 5 Vgt`ŅƫÓ3JZuŗМ5Ѫƚƭǩ0 FMO ɹжĭʥЩ

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SAR News No.27 (Oct. 2014)

FMO ЊĐϛΚϛʌЯ͆/̊J FMO Ѫƚƭǩ6 Đƚ5ĭƞͯŏEĐʢ Ѫƚѩ5ʒГȌ
3ƳȈ!.J ý5Vgt`ŅƫÓ5ZuŗМ5ɹжĭʥЩ3J FMO ѪƚƭǩNɁ.AJ0Ґū 5ґ ĭƞͯŏ3ˌ+(ѪƚƭǩĐǕǽHK.I Electron Density Server
ҐEDSґ3̠эK.J X ͹Ѫƚƭǩ0DŏΦ#J @( MP2 5ɹжĭʥЩH617β-estradiol 0ˀͧͯŏ#J Glu 05ѓ3tąɻϙˣK ŗМ5Ѫƚƭǩ˭2+.J0M+( ЧǛ5ˀͧͯŏNǳȞ#J His 06ɨH3̕2+.J[19] KH
5ͯʎ6 FMO ʥЩɹжĭ5ŃʇʥЩƦ҃±Ʀ0жŏ!.J0 FMO ѪƚƭǩʢC.
Ɣǲ/J0Nψ!.Jū 6 FMO Ѫƚƭǩ3GJ crambin ĺɻ̀5ϥÝҐTyr29ґH3 Ʀ͌ѓ/5Ѫƚƭǩsm5ɔëʽЖDЫC.J ū 6 6 crambin 5҇ĐϛΚʥЩ
Ґ0.48  PDBID: 3NIRґ5* 3 ,5aWJ Tyr29 3,. X ͹ƭǩ0 FMOƭǩNʽЖ!(D5/J[20] ŎaW3Ƴ!.ϟ͘K( FMO ƭǩNжđ3˝ŏ
#J03G+. Ʀ҃ë3С-.JʦƚMJ ¼ǻ6K3ϥÝєɔNƸā!ĺɻ̀
5ɹжëN˂CJ032J ¿3D FMO ƭǩN̊( 2Fo-Fc G9 Fo-Fc p5Ƹā2
13,.̂ůЫC.J
4

おわりに

IFIE NVx\ȵʧ0!(ZuҔʷźѓ̪³Ö̊5ϥÝ6 FMO ϟ͘5ƠƤ̣2Ė̊ˏ/J X ͹ʥЩϛʌ3GJЎѧȒż3Ģ. щƚĭƞ3ź-(Ƥщ̣2̪³Ö̊ȒżNǽJ0/J(C ğπ̶͋Ώ5ɝ 36ɭѭ m|]Ї0Zu05ąͯɳʥЩńK
(H@$6 FMO ϟ͘Nυ ̪³Ö̊ȒżNńǽ!.AJ0ØɝNīC!(Ґup[^ʥЩ3.Dőʦ/Jґ FMO ϟ͘6¼E̶͋Ƨ5 PC ]gmJ6waQ
5|ka/DȤЕ3ϟ͘/J>1БС32+.I ĔȃΏ/DØE# GUI DɕóK.J ƋI2ʥЩ͞ƭĭN!2.D Ω̣2s^ktN̊(ʥЩ5ĚĎ
̄Nυ+.7ƤỌ̏2Ȓż6ǽHKJ(C &K@/ȔϷ!.2+(̪³Ö̊5чϒȌ3ʿÀK(I ʥЩHǽHKJÃϯ3̄ϲ̣2ϋÀN¡J0/(I pt6Ƌ6$/JҐFMO2-MP2/6-31G NȾƒ#Jґ ̂ů IFIE smg5ʥ͚DʠϠ¥/J
 GI͞ƭ2̪³Ö̊5ΎưEĐƚsdS J6ĭƞłȈYwh5ϛɨ5(C36G
IƋϕʨ2ϟ͘Ȅϒ02IˑȔ˜ϒ˂KJ ̂˻/D2I5Ϩͪ2ϛʌ@//Jqɀ+.J @(¼Ŧ6ϜK2+( ˀś5Ţѷ3,.DĐƚsEЪͳ˧Ƙs3GJ̶͋ЫO/J[21, 22] ¼ǻ6 Ɖ5̶͋ΏũѨNȖ".JZuŗ

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SAR News No.27 (Oct. 2014)М5͞ƭʥЩˆƤEłȈ¥ȃ5tĭ˻ȗ21 щƚĭƞϟ͘NǒA3˕̊!(Ė̊ˏN̷
͏#J=̶͋NЫC.(0Ύ.JϵК
ʃ̶͋5ȾЫ3ĶĠѱ@!( ̄ĭƞ̶͋ȣ5ʃѓþЂý̈ ˢлĳҋĹƆ ˇǄ×̈ĹƆ ̽ȡƋƞ5̋¥ȞĈý̈ ͏ɐƋƞ5ɿɺ̼Ȇý̈ A$>Ȓżͷ̶ʖǬÉ̻5̤ʦ3Ȗϵ̎!@# @(ʃ̶͋6ɗп̓ƞ̫ HPIC Ƞ̓^5Đш 4 ʮ¢ÁD5-I5ɋɆNŅ@!(ĿΎɗ˽
[1] Kitaura, K., Ikeo, E., Asada, T., Nakano, T. and Uebayasi, M. Fragment molecular orbital method: anapproximate computational method for large molecules, Chem. Phys. Lett. 313, 701-706 (1999).
[2] The Fragment Molecular Orbital Method: Practical Applications to Large Molecular Systems, edited
by Fedorov, D. G. &Kitaura K.: (Taylor & Francis/ CRC Press, Boca Raton, FL, 2009)[3] Fedorov, D. G., Nagata, T., Kitaura, K. Exploring chemistry with the fragment molecular orbital
method, Phys. Chem. Chem. Phys. 14, 7562-7577 (2012).
[4] Tanaka, S., Mochizuki, Y., Komeiji, Y., Okiyama, Y. and Fukuzawa, K. Electron-correlated
fragment-molecular-orbital calculations for biomolecular and nano systems, Phys. Chem. Chem.
Phys., 16, 10310-10344 (2014).
[5] Ozawa, T., Tsuji, E., Ozawa, M., Handa, C., Mukaiyama, H., Nishimura, T., Kobayashi, S. andOkazaki, K. The importance of CH/pi hydrogen bonds in rational drug design: An ab initio fragment
molecular orbital study to leukocyte-specific protein tyrosine (LCK) kinase. Bioorg. Med. Chem. 16,
10311-10318 (2008).
[6] Ichihara, O., Barker, J., Law, R. J. and Whittaker, M. Compound Design by Fragment-Linking. Mol.
Inf. 30, 298-306 (2011).
[7] Fukushima, K., Kamimura, T. and Takimoto-Kamimura, M. Structure basis 1/2SLPI and porcine
pancreas trypsin interaction, J. Synchrotron Radiation 20, 943-947 (2013).
[8] Ohno, K., Mori, K., Orita, M. and Takeuchi, M. Computational insights into binding ofbisphosphates to farnesyl pyrophosphate synthase. Curr. Med. Chem. 18, 220-233 (2011).
[9] ɡʃĭƞÉȒżĭƞпÉϩҐCICSJ BulletinґVol. 31(2013) No.3, No4, ő Vol32 (2014) No.1
[10] BioStation (ABINIT-MP 7.0 BioStation Viewer 16.0) 6ϡcStHnTu/J
http://www.ciss.iis.u-tokyo.ac.jp/riss/dl/download.
[11] Nakano, T., Mochizuki, Y., Yamashita, K., Watanabe, C., Fukuzawa, K., Segawa, K., Okiyama, Y.,
Tsukamoto, T. and Tanaka, S. Development of the four-body corrected fragment molecular orbital(FMO4) method, Chem. Phys. Lett. 523, 128-133 (2012).
[12] Watababe, C., Fukuzawa, K., Okiyama, Y., Tsukamoto, T., Kato, A., Tanaka, S., Mochizuki, Y. andNakano, T. Three- and four-body corrected fragment molecular orbital calculations with a novelsubdividing fragmentation method applicable to structure-based drug design, J. Mol. Graph. Model.
41, 31–42 (2013).
[13] Fedorov, D. G., Kitaura, K. Pair interaction energy decomposition analysis. J. Comp. Chem. 28,
222-237 (2007).
[14] MIZUHO/BioStation3.0, Mizuho information and research institute Inc, 2013.
[15] Amari, S., Aizawa, M., Zhang, J., Fukuzawa, K., Mochizuki, Y., Iwasawa, Y., Nakata, K., Chuman,
H. and Nakano, T. VISCANA: visualized cluster analysis of protein-ligand interaction based on the
ab initio fragment molecular orbital method for virtual ligand screening. J. Chem. Inf. Model., 46,
221-230 (2006).
[16] Mochizuki, Y., Fukuzawa, K., Kato, A., Tanaka, S., Kitaura, K. and Nakano, T. A configuration
analysis for fragment interaction. Chem. Phys. Lett., 410, 247–253 (2005).
[17] Ishikawa, T., Mochizuki, Y., Amari, S., Nakano, T., Tokiwa, H., Tanaka, S. and Tanaka, K.
Fragment interaction analysis based on local MP2. Theor. Chem. Acc., 118, 937-945 (2007).
[18] Tsukamoto, T., Mochizuki, Y., Watanabe, N., Fukuzawa, K., and Nakano, T. Partial geometry
optimization with FMO-MP2 gradient: application to TrpCage. Chem. Phys. Lett. 535, 157-162(2012).
[19] Fukuzawa, K., et. al., to be submitted.

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SAR News No.27 (Oct. 2014)[20] Watanabe, C. et. al., to be submitted.
[21] Watanabe, H., Okiyama, Y., Nakano, T. and Tanaka,S. Incorporation of solvation effects into thefragment molecular orbital calculations with the Poisson-Boltzmann equation. Chem. Phys. Lett., 500,
116-119 (2010).
[22] Fukuzawa, K., Kurisaki, I, Watanabe, C., Okiyama, Y., Mochizuki, Y. Tanaka, S. and Komeiji, Y.
Explicit solvation modulates internal- and inter-molecular interactions within DNA: electronic
aspects revealed by the ab initio fragment molecular orbital (FMO) method. submitted.

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SAR News No.27 (Oct. 2014)///// Cutting Edge /////

YN̊(ɜϕQu`ŅƫÓȳȪπ5ğώʊĮπ̓Ƌƞƍ̋Ąϕ

はじめにgrSu6 &KH5ʥЩ5¥ȃ3Λ˧Ȍ5҇˱ĭˀͧ҅ʙNɻ!.I ˺̕
̣2grSuŅƫÓ3ͯŏ! ̈ÓʬΚNľƭ3ĘǾ!.J grSuÖ̊Nɻ#JıπŜ6 ǱĠ,Ɖǅ3Ö̊N̹#0HǜǤˋ̨̝̣/Ø̊K.I grSu҅ʙN
ŔBD50 ѭgrSuʥЩ5җ,5mS3ĐѺKJ ĚΏ6 ŅƫÓ05Ǳ̖ˀȌ̪
³Ö̊N˾ǽ/JĖ˲J ŅƫÓ5зȬȌ0˲/ŢѷNȭ.J ǻΏ6 ҇ŅƫÓзȬȌN˾ǽ/JD55 grSu˺ɻ5Ǎ҇̖ˀȌʥЩNʨê#J0
Ѩ! ŅƫÓ05ǱͯŏNǽJ06ƫɩ/2Ґū 1ґ ҇̖ˀȌN̹#Ǎ҇ĭŏ
˹0!.QnmȶHKJ ĭŏ˹5ʥЩG9ŏȞ0˲/ grSuĭŏ˹
5̖ˀȌʥЩ0!.6ɹж062 &5G2¥/ ˱ͧŔɻTͧ]gm5,0!.ŇH̳HK.JY3ˑ̨!( Y6 ˳ʬĭƞΏN¥ȃ3Tͧ¥ȌƚύЍ̝ˏ<5Ȉ̶̊͋̦O32K.( 1) ȟ 6 Y5ʮúʥЩG9҇̖ˀȌNğπ<Ė̊#= ẓ̸́2ğπȼͨHıπèύĭŏ˹5ğώ@/ǜǤ̶͋Nǁђ!.( /6 YN̊(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
Y6 ²ĲѮÓʥЩ5 12 æ5ѱ˲3 2 ,5˱ͧĽƚ0 10 æ5TͧĽƚÐΆ!(ʥЩNȴ,ĭŏ˹/ Ă.5˱ͧ0Tͧ3ˀͧĽƚͯŏ!.J(C ƈï6 12 æ5ˀͧ
Ľƚ/ϓMK.I˱ĭˀͧ0ő͕5҇̖ˀȌN̹#Ґū 2ґ @( ĭƞ̣3ʢC.ƠƤ/I 2 ,5˱ͧĽƚ5ÐΆ5в3GI Xt m | 3 ͇5̕ȌÓƜů#J0
Hʮúj0DÙHKJ ɷ3 ˂ʗłȈE˂ѪƚłȈ ъǂϜƘ3GJYp^łȈ21 ЧǛ5ɻʬŏȞłȈж̊/J ÆȔ5˱ͧĽƚETͧĽƚ3зỌ̃̄3ΆɄźNƸā!(ĭŏ˹<ϬƸ#J0ňΚ/J 1) 5G3 ŏȞ ͞ώG9âƜ@/ ЧǛ5ɻʬĭŏ˹0ő͕3ȥ0/J0H ȟ 6Yıπĭŏ˹5̖
ˀȌPaWQ0!.Ė̊/J0Ύ( ˺3 ҇̖ˀȌ0˺ạ̏2͏ÓʥЩNɻ#JgrSu҅ʙ5пNY/ΆɄJ0/ ѭgrSuʥЩNɻ#Jĭŏ˹3
Ǳ̖ˀȌ̪³Ö̊NÀ¡! grSuŅƫÓҔZuϏŏÓNƠƤĭ/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Qu`6 AR <5ͯŏN½!̏Ȍ5̈̄ʬΚE͖Γ5̟б21Nà#̏ȌgrSu    /  J ̈ Ó ĉ Q  u  `  6 testosterone Ґ TS ґ  G 9 & 5 Á ϵ ˹ /  J
dihydrotestosteroneҐDHTґ/JҐū 1ґ DHT 0 AR 5ͯŏʦǬ6ąͯɳʥЩHɨH02+.J 4) DHT 5Ywź6 AR 5 Arg752 G9 Gln711 0 ˀфź6 Asn705 G9 Thr8770ˀͧͯŏNǳȞ!.I grSu҅ʙ6KHˀͧͯŏȌƣΚź5͌ѓсΆ0 AR 5̖ˀȌ_pt05̖ˀȌ̪³Ö̊3є¡!.JҐū 3ґ AR 6ʗĉŅƫÓ/I ZuͯŏѴŷ3̈ÓĉQu`ͯŏ!(ǻ ͇ 5aQ]om0ДċŧƚϏŏÓNǳȞ#J0/Qu`Ö̊N̟Ʌ#J 5ɮ AR 5 12 ̨̔5<p]gҐH12ґQbwg
tсǪ32J0 aQ]omͯŏ!ДċàЫKJ ɝ Zu5ͯŏ3GI
H12 QbwgtсǪN0K2Žŏ6 aQ]omͯŏ/$ŅƫÓ5˕ȌĭȨĘ
K &KH6Qmbwgt0!.ʬΚ#JҐū 3ґ
Сǟ ̻É5҇ҏĭ0ѽ̈˕5ʯ͜ĭ3Ë Ě͏Ο̞5·Ȑ̀0ʶ¶̀5ȋˬ2ƃĢŢѷ
02+.J Ě͏Ο̞5>0O16Qu`ÜƜ̣3ƃʸ#J(C AR Qmbwgt
&5ˋ̝3Ǥ̊HK.J 5) Ě͏Ο̞ˋ̝π/J flutamide 6 &KΤБD AR 3ͯŏ#J Óĉ/˕ȌÁϵ˹/J hydroxyflutamide 3ƇɄK(5* AR 3ǱĠ3ͯŏ#J &/ ɜϕ AR QmbwgtNğώ#= UwY҅ʙN AR Qmbwgt5
PaWQg[Wu0ϕƤ! j̆G9Y˱ͧΆɄźNȼͨ!( ĭŏ˹5Y AR 5̖ˀȌ_pt0Ǳͯŏ! , Y5͏Ọ́Ǎ҇3GI H12 QbwgtсǪ32J0NјƩ/K7 KHĭŏ˹ǱĠ2 AR Q
mbwgt0!.Ö̊#J0NʀǺ!( &5ͯʎ hydroxyflutamide GIDǱĠ2 AR ͯŏΚG9 AR Qmbwgt˕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[^eeH BA341 5eQyź Gln711 G9 Arg752
0ˀͧͯŏNǳȞ!.J0̹şK(Ґū 5ґ @( }u[eoź6 Thr877 G
9 Asn705 5ïюYwź0ˀͧͯŏNǳȞ!.I DHT 0 AR 5ͯŏʦǬ0>?őʦ5
ͯʎǽHK( 3DMH$ DHT 0̕2I AR Qmbwgt0!.ʬΚ!(06ѭǛ3ΧŘ˜ Y AR 5 H12 QbwgtсǪNńJ0Nƕ.J0ΎHK( up[^5ͯʎH H12 5ʥȞQyф/J Met895Ґū 5, ]ґ5ʷź BA341
5Y̆3ȽС!.I Y5Ǎ҇ H12 NQbwgtсǪHȹѝ!(
0Qmbwgt˕Ȍ3ͯ9,(0ΎHKJ ,@I BA341 5Y̆6 gr
Su҅ʙ5҇̖ˀȌ5ʹȴ G9͏Ọ́Ǎ҇3GJQmbwgt˕Ȍ5̟̂5җ,5ǸĞN˨".J0ɨH02+(

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 Qmbwgt˕Ȍ5̟̂36 AR 5 H12 QbwgtсǪNʹȴ/22JG2
ZuʥЩчϒ/J0H H12 Сñ3ÐΆ#J BA341 5}u[eoźпÐ5
ʥЩäѿNϦA( @( AR 5 Asn705 G9 Thr877 05ˀͧͯŏNΎȚ3āK ˀͧͯŏȌƣΚźNɻ#J 1a-1h NŏȞ!ΆɄź5ǷѰ3,.ʠϠ!(Ґψ 1ґ ˀфźNɻ#JϬƸÓ
1a-1d 6 BA341 GIίǝ AR <5ͯŏ6Ñ!(D55҇ͯŏΚN̹!( ɝ _tϬƸÓ 1f 1g G9V[eϬƸÓ 1h /6 AR 3Ƴ#JͯŏΚ6Ѹκ3Ñ!( 5ͯʎ6
BA341 5}u[eoź5пĐ3ˀͧͯŏuv5Ɯůчϒ/J0N̹!.I
up[^eeH°ˣK(̪³Ö̊ҐAsn705 5Ywź05ˀͧͯŏґ
0DΦ#J AR 5Дċ˕ȌĭϦ҃/6 }u[eϬƸÓG9YwϬƸÓ$K3
.DƸā!(ΆɄźƋ2J0˕Ȍ5ÑϔHK(Ґ}u[eϬƸÓқBA341 > 1a
> 1b 2 ΆɄ}u[eϬƸÓқ1c > 1d YwϬƸÓқ1e > 1f > 1gґ @( Qs}uϬƸÓ 1e  BA341 0>?ő"5 AR ͯŏΚG9 AR Qmbwgt˕ȌN̹!(̄̌6ɨ̷/62 Y5ѪƚŕǭȌ3GI˕Ȍĭ!(Ywźˀś!.J021ΎHKJ BA341 5eQyź6ˀͧͯŏQ]im0!. Arg752 0 Gln711 0̪
³Ö̊#J &/ ĭŏ˹ 1c 5eQyźNGISgƁźȌ5҇Qioź<ƇɄ!(0L AR 3Ƴ#JͯŏΚ6ʹȴ!(D55Дċ˕ȌĭΚ6Ѹκ3Ñ!( ˀͧͯŏ5ɝœ5ƇĭEQioź5oпĐ3GJ͏ÓѣƩ21 ĭŏ˹0 AR 5ͯŏʦǬĂÓ3ǷѰN¡
.J0ΎHKJ-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	 aTris ͻχ˛3 hAR-LBD [3H]-DHT Ϧ҃ĭŏ˹NĢ 4 oC / 15 ɮѓS[e!( &5ǻ DCC /Ď̄!дȃĐѧ!(˞3Ŕ@KJ AR ͯŏ[3H]-DHT 5ɍƶ˕ȌNˣƤ!( Binding affinity 6 DHT 5 AR-LBD <5ͯŏN 100 0!(ɮ5̪Ƴͯŏ̀0!.͘ďK(b
NIH3T3 ͪΘ3 hAR ̟̂gu0 AR Ȉ͗сēNŔB Luciferase ̟̂guNͭAОA DHT G9Ϧ҃ĭŏ˹NĢ 5% CO2 Ɯů 37 oC / 24 ɮѓS[e!( &5ǻ eUj˕ȌNˣƤ! AR 5˕Ȍĭ̀0!.Ʉ͘!( ǽHK(˭ǩÜƜɶ͹H IC50 N͘ď!( Дċ˕ȌĭϦ҃/6 Ϧ҃ĭŏ˹ AR <ͯŏ!
(ǻ H12 5сǪƇĭN½!( AR 5˕ȌĭјƩ5͆ǩłɪKJ(C AR binding affinity 0̪є!2ŽŏDJ

AR フ ル ア ン タ ゴ ニ ス ト の 設 計 と 創 製
Flutamide 5яʀȩ¡3GJĚ͏Ο̞ˋ̝/6 flutamide 3GIĚ͏Ο̞ƃʸȑĭ#J
Androgen Withdrawal SyndromeҐAWSґN̛̟#J0̳HK.I AR 5 Thr877  Ala 3
Ƈ̕!( mutant 5̟̂̷ϪK.J 7) Flutamide E hydroxyflutamide 6 T877A Ƈ̕ AR
36ͯŏ#JD55 Thr877 05ˀͧͯŏǳȞ/2(C &5Сñ3ÐΆ#J H12 ƫɩ
3QbwgtсǪ32I AR N˕Ȍĭ! AWS NǭЉ#0ΎHK.J ̂ů AWS 3
6 Ƈ̕ AR 3DQmbwgt˕ȌN̹# bicalutamide Ǥ̊HK.JҐψ 2ґ8) BA341
6ǱĠ2 AR ͯŏΚN̹! AR ÜƜ̣3ƃʸ#J SC-3 ͪΘ5ƃʸNʢC.Ñ˭ǩ/ȨĘ#J0HĚ͏Ο̞ˋ̝5èύĭŏ˹0!.ʀǺK( ʷȉ203 BA341 D flutamide 0őʦ T877A Ƈ̕ AR N̟̂!.J LNCaP ͪΘ5ƃʸNàЫ!( BA341 5}u[eoź6 Thr877 0ˀͧͯŏNǳȞ!.I Ala <Ƈ̕!( AR /6ˀͧͯŏǳȞ/$ H12ÀС/5ĭŏ˹5ͯŏʦǬƋƇĭ! LNCaP ͪΘ3Ƴ!.QbwgtÖ̊N̹!(0Ύ
HKJ Bicalutamide 6 flutamide ʦ5ʥЩ3яïюʥЩƸāK.I Thr877 05ˀͧͯŏǳȞK2.D 5пĐ H12 3̩Ƚ̣3͏Ół̟ND(H!.J &/ BA3415}u[eoźŗМ3͏Ọ́3Ǎ҇ïюNƸā#J00!( ĚУ!(G3 5пÐŗМ/6oź5G2ΆɄźϣƫKJ0H oN½!.UwïюN
Ƹā!(ĭŏ˹ 3a-3d 4a-4d 5a-5b NŏȞ!(Ґψ 2ґ

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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	 Y0!. O E S Nɻ#JϬƸÓ 3a-3d G9 4a-4d 6 bicalutamide GIÑ AR ͯŏΚN̹!( QitQuźNɻ#J 3d G9 4d 3Ǳ AR ͯŏΚϔHK( !!2H Ƈ̕ AR ʖ LNCaP 3Ƴ#JƃʸȨĘ˕Ȍ6 3a-3c G9 4a-4b 5ɝ bicalutamide E 3d
4d GIDǱĠ/+( KH5ͯʎ6 ŏȞ!(ĭŏ˹0 bicalutamide 5YпÐ̕2
J0E AR  wildtype  T877A mutant 5в3Љŧ#J0ΎHKJ ͳ. bicalutamide
0ő" SO2 YNɻ#Jĭŏ˹ 5a G9 5b 5˕ȌNϥÝ!(0L bicalutamide GID
Ñ AR ͯŏΚN̹!( ˺3 QitQuźNɻ#J 5b 5 AR ͯŏΚ6Ѹκ3Ñ!(
H3ΧŘ˜03 5a G9 5b ą3 LNCaP ͪΘ3Ƴ#JƃʸȨĘĥʎ6ϔHK2+(YŔɻĭŏ˹/6 Y̆5҇̖ˀȌ̪³Ö̊ö(C bicalutamide 06̕
2JʦǬ/ AR 3ͯŏ!.J0°ȓK ĂÓ0!. bicalutamide 0Ƌ̕2JʥЩ˕Ȍ̪є3Υ+(0ΎHKJ
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KƖC ЧǛ5Ě͏Ο̞)/2 AWS E BWS 3Dɻĥ2ȪQu`5ђ̟ɤȋ3˂
CHK.J 9) ĭŏ˹ 3b G9 4b 6 bicalutamide 5ʥЩNź3sdS!.I bicalutamide0Î(G2ĥʎN̹#0ΎHKJ BWS 5Ľŧ02J AR 5 Trp741 5Ƈ̕3Ƴ!Y̆ȤʬΚ#K7 BWS 3Dɻĥ/L $K3%G AR 5QyфƇ̕Nʿ3!2HQmbwgtNğώ!ͳJ56 Smo+ő˴/J &/ȟ 6 H12QbwgtWNńH2G ͏Ọ́3Ǎ҇Y/ H12 G9&5ŗМN̩

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SAR News No.27 (Oct. 2014)

ȽјƩ#JG2ĭŏ˹NΎʚ!( #2M* AR 0 BA341 5eQyź5ˀͧͯŏN^iʥЩ/ʨê#J03GI PaWQ/JUwYʥЩGI H123ȽС!(ɜ(2mS5 AR Qmbwgtğώ/J0ʀǺ!(Ґū 6ґ10) @(^iź36ˀͧͯŏňΚ2пÐǢ,Ɯů#J(C eQyźNɻ#Jĭŏ˹GI
DǱ AR 3ͯŏ#J0ΎHKJ /6 ^iϬƸÓ3Ƴ!.ǽHK(ͯʎ5пNͫ½#J ŏȞ!(^iϬƸÓ 6a-6c 6$KD AR 3ͯŏ!( fXʥЩ
NQit/âϸ!(ϬƸÓ 6d 6 AR 3ͯŏ!2+(Ґψ 3ґ K6 ĭŏ˹5^iź AR 5Qyфʷź0̪³Ö̊!.JϤȱ/I ʃĭŏ˹sdS5ƔǲȌNɋȴ#JʢC.чϒ2ͯʎ/J T877A Ƈ̕ AR N̟̂!.J LNCaP ͪΘ3Ƴ#JƃʸȨĘΚ6Y3ΆɄź52 6c /Dǰ2HϪCHK( @( &5˕Ȍ5Ǳ6Y
̆HďJïю5я3ÜƜ!Ґ6a > 6b > 6cґ6a 6 bicalutamide 0>?ő͕5˕ȌN̹!(
ʃͯʎ6 Y̆ H12 N̩Ƚ̣3јƩ!.J0N̹ş!.J KH5ĭŏ˹
6 bicalutamide 0Ƌ̕2JʥЩNɻ!.I BWS 3Ƴ!.Dɻĥ0ΎHK ¼ǻ5ϥÝͯʎ3ʀǺ!(AR Qmbwgt3GJĚ͏Ο̞ˋ̝/6 ͖ͭ΄/5 AR 5Ö̊ȨĘKJ03GJ
͖щ5ÑŢѷ02J0DJ Ȫ AR π5ĜÖ̊5Еˡ36 ȪQu`Ö̊0Ȫm
|]őĭÖ̊5Đѧ ňʭ/I ͭ΄зỌ̃̄Qu`ŅƫÓĘǾπҐSARMґD@(̦O3̶͋2K.J Ϩͪ6У=2 ȟ 6YNĖ̊!( SARM 5ȼͨDЬυ!.I AR |eQbwgt215ğώ3DȞġ!.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/6 ɜϕ̖ˀȌPaWQ3̨̰!(ğπ̶͋5¥5 AR Qmbwgt5ğ
ώ3,.ͫ½!( ɹС/6 ¤υ!.ЫC.JY5˹̄ĭƞ̶̣͋Hɜ(2˺ȁN̟ϔ! ÀĢÝëNȴ(%(Ʀ̣̊2ıπèύĭŏ˹5ğώ<0̶͋ĉƫNͅ!.J ð˴ȌƋ2ϒͧ/+(ğπ0Đш36 ̓ƞ5Ыʳ3GIϲ̣̄ϒͧĢM+( ʂ)3ͲƳ̣2ıπŜђ̟5Ȥˏ62 K3,.6 ̂ů5ğπȤˏ5ƉʦĭNϔK7ͥǽ/J/L Structure-Based Drug DesignҐSBDDґ Fragment-Based Drug DesignҐFBDDґ
Computer-Assisted Drug DesignҐCADDґ21 Ɖɔ5ȤˏɂŠK.J̵̧5ɝˏNз;56ʢC.Ѩ! ɹɜ5ğπȤˏDΪ ŇHĖ̊K.JD5N̕2+(ϖ˲Hϔ̩#0Dчϒ/62)L
ĿΎɗ˽
1)

Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F.-G.; Barth, R. F.; Codogni, I. M.; Wilson, J. G.
The chemistry of neutron capture therapy. Chem. Rev. 98, 1515–1562 (1998).
2) Ohta, K.; Goto, T.; Fujii, S.; Kawahata, M.; Oda, A.; Ohta, S.; Yamaguchi, K.; Hirono, S. and Endo,
Y. Crystal structure, docking study and structure-activity relationship of carborane-containing
androgen receptor antagonist 3-(12-hydroxymethyl-1,12-dicarba-closo-dodecaboran-1-yl)
benzonitrile. Bioorg. Med. Chem. 19, 3540–3548 (2011).
3) Goto, T.; Ohta, K.; Fujii, S.; Suzuki, T.; Ohta, S.; Endo, Y. Design and synthesis of potent androgen
receptor (AR) antagonists bearing a p-carborane cage: Promising ligand for anti-androgen
withdrawal syndrome. J. Med. Chem. 53, 4917–4926 (2010).
4) Bohl, C. E.; Miller, D. D.; Chen, J.; Bell, C. E.; Dalton, J. T. Structural basis for accommodation of
nonsteroidal ligands in the androgen receptor. J. Biol. Chem.280, 37747–37754 (2005).
5) Neri, R. Pharmacology and pharmacokinetics of flutamide. Urology 34, 19–21 (1989).
6) Fujii. S.; Goto, T.; Ohta, K.; Hashimoto, Y.; Suzuki, T.; Ohta, S; Endo. Y. Potent androgenantagonists based on carborane as a hydrophobic core structure. J. Med. Chem. 48, 4654–4662(2005).
7) Suzuki, H.; Akakura, K.; Komiya, A.; Aida, S.; Akimoto, S.; Shimazaki, J. Codon 877 mutation in
the androgen receptor gene in advanced prostate cancer: Relation to antiandrogen withdrawal
syndrome. Prostate 29, 153–158 (1996).
8) Fradet, Y. Bicalutamide (Casodex) in the treatment of prostate cancer. Expert Rev. Anticancer Ther.
4, 37–48 (2004).
9) Yoshida, T.; Kinoshita, H.;Segawa, T.; Nakamura, E.; Inoue, T.; Shimizu, Y.; Kamoto, T.; Ogawa,O. Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostatecancer xenograft model derived from a bicalutamide-treated patients. Cancer Res. 65, 9611–9616(2005).
10) Kaise, A.; Ohta, K.; Fujii, S.; Oda, A.; Goto, T. and Endo, Y. Design, synthesis, biologicalevaluations, and docking study of glycerol and aminoglycerol derivatives containing a p-carborane
cage as novel androgen receptor full antagonists. To be submitted.

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. ϴ˨υMKJ°Ƥ/# ɭѭƉ5̤ʦ5ĿĢNѹ̎!@#-26-

SAR News No.27 (Oct. 2014)///// Activities /////
ҜÉŖҝ
͒ 42 Ŧ ʥ Щ ˕ Ȍ ̪ є e   f T ɡɮқǞȞ 26 ǟ 11 ɺ 13 ɡҐʁґ14 ɡҐъґÉŽқ@D0ʞрȃdҐ860-0047 ˶ʃ̬˶ʃǔϑİɫɡ 1-14-1ґ§ôқɡʃπƞÉʥЩ˕Ȍ̪єпÉǻɆқɡʃĭƞÉғɡʃЛήĭƞÉғɡʃĐʌĭƞÉғɡʃЛπƞÉғɻʬŏȞĭƞĶÉ
͒ 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 simulationsĐƚħĠƞeeN̊(ш̈ųƇ̕ų CYP1A2 5͏ÓʥЩG9ʥЩʒГȌ5°ˣҐ1 ъˉƋќıπâғ2 ʊĮƋќπғ3 ĮцƋπғ4 їƋς̶̡ґˢлŁц˄ 1ғ̿Őä 1ғÈρѥ 2ғǞſ̭Ǯ 2ғǄ¬ɐ© 3ғǤшä 3ғƹ̋ǶŊ 1, 4

KO02

Non-empirical analysis of metabolic reactions of thioridazine by Cytochrome P450 2D6Đƚ̓ƞϟ͘N̊(oXnf5 CYP2D6 3GJÁϵЯ͆5ѭ̣ͮ҃ϛʌҐIґ
ҐȀǉƋќπґ͓Ľÿęғ҂ǉǵғŐ̋бϼғ¥҂ƯKO03

Development of in silico prediction model on environmental fate of chemical substances̆Ƃ¥3Jĭƞ˹Ї5ĢˀĐϛȌ°ˣegr5ʥ͚
Ґ1 їƋќπғ2 їƋǿ̈˹̶͋̚ȣґƟʘ̅ 1ғǆʃɯĈ 1ғƨǋƋЂ 1ғǏ̄ɡ» 1, 2ғ҇ʁб­ 1, 2

11:15 - 12:05
KI01

Ȱ Ǻ ϴ ˨ Ґ É Ž қ   d    ґ  Ǫя қ ˁ̋ƻ­Three-dimensional protein structure and dynamics in living cells
̈(ͪΘĉ/5ς̡Ї5͏ÓʥЩ0nSv]gҐҁрƋƞʊ¹ ̄ǐƞ̶͋̓ґ˅ϹьĆ

13:30 - 14:30
KO04 Ω ϴ ˨ Ґ É Ž қ   d    ґ  Ǫя қ҇ʁб­Structure-activity relationship of ecdysone agonists bearing imidazole skeletonSnl͠Ν̥Qbwgt5ʥЩ˕Ȍ̪єҐ¹ƋќЛґʩµƋ˓ғķˈ͡ғ̵ſĳеғ¥ǏƓ͂ғƨǏȎ

KO05

3D-QSAR study of neonicotinoid insecticides having a substituent on the 5 position of theimidazolidine ringSnlf̆ 5 Ð3͇

5ΆɄźNɻ#JSn]uѺͽÓ5ŏȞ0ʥЩ˕Ȍ̪єϛʌ
Ґ1 ȕƙƋЛғ2 ¹ƋќЛґϑΜƴ 1ғяǆ8J 1ғЈʋΉ͡ 2ғǄĉΒ 1ғҁρΊĹ 1

-27-

SAR News No.27 (Oct. 2014)

KO06

Preclinical evaluation of COPD by means of hyperpolarized 129Xe MRIЊíʢ Xe MRI 3GJșȌёƀȌΖ̙ȐҐCOPDґ5ĚΣǥϥÝ
Ґ1 їƋќıғ2 ¹ƋќȒżґʁʆɒ΢ 1ғǄĉͩЉƚ 1ғƑʆȘƍн 1ғ¼µƢǴ 2ғρĽαɨ 1
14:40 - 16:40

gmipe ҐÉŽқSVґ

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 ¼µЙƚHow to predict the diversity of drug-induced liver injury?
π˹ȌΔѣƩ5ƉʦȌ<5ƳȈ0°ˣҐŒŇǀƋƞƋƞќıƞ̶͋̓͠ґʩµʺ

18:30 –

ȜϘÉ ҐÉŽқrwXmw˶ʃґ-28-

SAR News No.27 (Oct. 2014)

 g m  i p e    [11 ɺ 13 ɡ
KP01

Synthesis

and14:40 – 16:40] Ґ É Ž қ   S V ґstructure-activity

relationshipof

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 ɬśƋґƨŶζʂǖ 1ғΙƋS 2ғдρɴŊ 1ғ
γµόЂ 1ғʋˁá© 1ғ´ĲцǶ 1ғʛ̋Ǝ 3ғĽɨ 3ғŏ̋˙ɨ 4ғϺǆƻʪ 2
KP02

Discovery of thienopyrimidinone derivatives as a new series of potent phosphodiesterase 7
inhibitors
ǱĠ2 PDE7 јƩ˕ȌNɻ#JɜϕoVyfyϬƸÓ5ğώҐ̶̓ώπґдρĦ½ғˊŏîƍнғ˗шʲōғƌш¢ˋғ˫̋ŰИғƼ͡ƚғ҇ʫÌɨғŮ̋џғ¯µ˦ªғˁ̋ƻ­

KP03

Analysis of inter-molecular interaction between kinase domains required for transphosphorylation of receptor tyrosine kinaseјƩěΐȌƇ̕Óoe[vj0јƩě05̪³Ö̊5ϛʌ
Ґ1 ˶ʃƋπғ2 Į˚аƋғ3 SVƋƞґ¡Ǫ҉ɚ 1ғƹʫǏɓĹ 1ғʞǆǮȆ 1ғƌшÌˋн 2ғʩǏ̭ʜƚ 2ғJoseph Schressinger3ғ͈ŴčǴ 2

KP04

Identification of ligands of DJ-1 with biophysical screening˹̄ĭƞ̣ȤˏN̊( DJ-1 ƹĐƚĭŏ˹g]w^
Ґ1 ʊƋќɜѴŷğȞ̓ƞғ2 ʊƋќǐғ3 ʊƋı̶̓ґ̋Áɰ­ 1ғJose Caaveiro2ғяѐ̵ɵ 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}tG9cY[eVgrj 2 уͧ5 1 QyфƇ̕3GJźЇͯŏпÐ5ʥЩƇĭ0źЇϪϷȌ5̪в
Ґ1 ˶ʃƋπғ2 Qg~XPғ3 ̉ͷ̶ґµǏ×© 1, 2ғρĽɘ­ 1ғϑ˫е 1ғ
Ƌ˘ηÁƚ 1ғǤǏЂʮ 3ғ¼µЙƚ 1

KP06

Fish toxicity prediction of chemicals using atomic fragment method: Global parameters andchemical group parametersĽƚ^tˏN̊(ĭƞ˹Ї5ҊʼȌ°ˣқ˃̊|m0æĕ|mҐϺʫȧ̓Ƌќǐґ˅ό²ғ҇ʫ̌ѥ

KP07

Study on binding of sodium phenylbutyrate to human serum albumin
UwтфvtT5τ˞Qͯŏ˺Ȍ3є#Jẓ̸́ʠϠ
Ґ1 ǊŶƋπғ2 ǊŶƋќπґǄǋţ© 1, 2ғʤ̋˒½ 2ғǆʃÚƚ 2ғ̋ņśɨ 1ғƨʃ̀ 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 ɬśƋπґƹ˫ɜн 1ғŏ̋˙ɨ 2ғǤшä 1

KP09

Partial similarity analyses of ligand-binding sites on proteinsm|]Ї¥5ZuͯŏпÐ5пĐѺÎȌϛʌҐĮцƋπґǄ¬ɐ©ғǤшä

-29-

SAR News No.27 (Oct. 2014)

KP10

Structural predictions for small proteins by using molecular dynamics simulationsĐƚħĠƞˏ3GJƹm|]Ї5͏ÓʥЩ5ȾƤ
Ґ1 ъˉƋќıπâғ2 їƋς̶̡ґƹ̋ǶŊ 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(C5Zug{og]w^Ȥˏ5ђ̟Ґ&
5 4ґқʥЩRZt5ɌΪҐĮцƋπґоō¨ȏғϑ͐έǴ

KP12

The construction of a pairwise database of ChEMBL ligands with 3D superimposition andstructural transformation application
ChEMBL N̊( 3D ч4ŏM%smgʥ͚0ʥЩƇɄ<5Ȉ̊Ґ̶̄ CLSTґʫʃțɨғǠ̲ғʃѓþЂ

KP13

Comparative analysis of intermolecular interaction of influenza neuraminidase with sialic acidsubstrate and its analog inhibitorsϜƘłȈʬʥ3ź-(SVdySwnj0eQфϬƸÓ05̪³Ö̊ϛʌҐȀǉƋќπґά̋Ѥ̠ғŐ̋бϼғ¥҂Ư

KP14

LERE-QSAR analysis of papain and trypsin hydrolysis of a series of substituted phenyl
hippurate esters҂ƽфUwVgr5egrS0irQj5ĢˀĐϛłȈ5Đƚ̓ƞϟ͘3GJϨͪϛʌҐIґ
ҐȀǉƋќπґåʫɧƋғ҂ǉǵғŐ̋бϼғ¥҂Ư

KP15

LERE-QSAR analysis on complexes of HIV-1 PR with a series of allophenyl norstatin
inhibitorsĐƚ̓ƞϟ͘N̊( HIV-1 protease 0QUwygmo҅ʙNȴ,ĭŏ˹05ϏŏÓ5͞ƭ̪³Ö̊ϛʌҐȀǉƋќπґʍɓ¨ғшΜѬғŐ̋бϼғ¥҂Ư

KP16

Use of expanded perception of protein-ligand interactions as a fingerptintϨͪ2ѭͯŏ̪³Ö̊ϪϷ5 Fingerprint 0!.5Ė̊Ґ1 Q]igʖǬÉ̻ғ2BIOVIA corporateґ҈ǆѤō 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 QSARҐĮцƋπґŐ̋ɴŤғǤшä

KP18

Fragment based drug discovery (FBDD) vs molecular evolution: Shared strategy for the
induction of substrate/target selectivityҐ1 esRZʖǬÉ̻ғ2 їƋ JST ERATO ΛЇ˕ȌʥЩfU]tғ3 їƋќ̄ғ4 їƋź̸̄ƞfU]t̶͋imґǔĽŃ 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-({vj-{gmϏŏÓ5ͯŏΚϥÝҐĮцƋπґ˞̋˒΢ғǌȞΉғ͑̋-ȆҌ̭̌ƚ

-30-

SAR News No.27 (Oct. 2014)

KP20

Protein active site comparison with SiteHopper: Phylogeny to polypharmacology
Ґ1 XQSf|ʖǬÉ̻ғ2OpenEye Scientific Software Inc.ґÒρ̀υ 1ғ
Gregory Warren2ғPaul Hawkins2ғJ Michael Word2ғTom Darden2ғRobert Tolbert2

KP21

Study of novel series P2X3 receptor antagonists: Structure-activity relationships ofpyrrolinone derivatives using homology modelɜϕ P2X3 ŅƫÓQmbwgt5̶͋ -fsN̊(yϬƸÓ5ʥЩ˕Ȍ̪єҐƁшΊώπҐʖґґʕĽƐ͸ƚғɥîƍнғ̽̋˒ǴғѼˁό©ғ¯ǄЂ©ғ
̍ə˙Ǡ

KP22

Development of the protein-gene sequence motif analysis system based on the codon reduced
representationau΁͢ψ̂3ź-m|]ЇҔиÊƚсēoϛʌegr5ђ̟ҐϺʫȧ̓ƋќǐґǄʃ˪źғĢρĹɨ

KP23

Mechanism for producing structure and functional variation of short chain dehydrogenase/reductase (SDR) family proteinsShort chain dehydrogenase/ reductaseҐSDRґPς̡Ї5ƉʦȌ˾ǽʬʥ
Ґ1Ґ˼ґЛʡ̈˹Є˥̶͋ȣ

KP24

2

Ґ˼ґЛʡ̆Ƃȧφ̶͋ȣґĚ̋Ή͡ 1ғ¥ãǮ 2Computational study on the interaction of high affinity binding ligand, calystegineB2 with
β-glucocerebrosidase
β-glucocerebrosidase 3Ƴ#J҇ϘśȌZu calystegine B2 ѺͽÓ5ϟ͘ĭƞ̣̪³Ö̊ϛʌ
Ґ1 ĮцƋπғ2 ƮǄƋ̚ќπґ¥Оˎ 1ғĢρɒ 2ғŐ̋ɴŤ 1ғǄ¬ɐ© 1ғЍ͏ÈǑѤ 2ғǤшä 1

KP25

Off-target search with large-scale virtual screening data generated by the K supercomputer
projectƋϕʨ{og]w^smNĖ̊!(Xm`ptȼͨ
ҐQg~XPʖǬÉ̻ґŭʃºғǆʃɒ©

KP26

Development of the structural feature analysis system for molecules based on the threedimensional neighborhood informationʮúСñȒż3ź-Đƚ5ʥЩ˺ȁϛʌegr5ђ̟ҐϺʫȧ̓ƋќǐґÒЃĦŝғĢρĹɨ

KP27

Relation between eigenvector of molecular matrix and atomic environment of moleculeĐƚυē5Ŭɻ]t0Đƚĉƾȣ̆Ƃ5̪єҐϺʫȧ̓Ƌќǐґʞº̭ғ҇ʫ̌ѥ

KP28

Development of integrated drug database and analysis of rhabdomyolysis by ATC codesıπŜͱŏsmg5ÖȞ0 ATC au3GJʩ͖ͤσϛ̛5ϛʌҐєϑƞќƋ̄ǐґƋʞ͡»ғŻǏωȆғǆ̋Ɲ

KP29

Development of substituent conversion database and searching system for medicinal chemists“CUES”: Convert it Unique and Elegant Substructureğ π ĭ ƞ Ώ 5 ( C 5 ʥ Щ Ƈ Ʉ s  m   g CUES: Convert it Unique and Elegant
Substructure 5ђ̟0Ȉ̊
Ґ1 Ǘ»Pғ2 ̶̄ґ˶˫ţƚ 1ғÒ

-31-

ʁáƍ 1ғǠ̲ 2ғʃѓþЂ 2

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 ʃѓþЂInvestigation of dispersion interaction on complex formation of ligand with protein:
Quantitative assessment of binding interaction energy in the LERE-QSAR analysis
ZuҔm|]Ї5ϏŏÓǳȞ3JĐɑĠ̪³Ö̊5ʠϠ: LERE-QSAR ϛʌ
3Jͯŏ̪³Ö̊Vx\Ѳ5Ƥщ̣ϥÝҐȀǉƋќπґŐ̋бϼғʍɓ¨ғåʫɧƋғ҂ǉǵғ͓Ľÿęғ¥҂Ư

KO08

LERE-QSAR and LIE analyses of binding affinity of γ-lactam hydroxamic acid derivatives withtumor necrosis factor-alpha converting enzymeΞ̜ƅʶŧƚαƇɄуͧ (TACE) 0γ-]m}u[cфϬƸÓ5 LIE ˏ3źϛʌғLERE-QSAR ϛʌ0ʠϤҐȀǉƋќπґшKO09ΨғˮшͶмғǈùÖғŐ̋бϼғ¥҂ƯNovel protein structure alignment method based on the residue-residue interactionʷźѓ̪³Ö̊3ź-ɜ(2m|]ЇʥЩQStˏ5ђ̟ҐĮцƋπґƲǘ˿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 bayesianprediction models based on the KINOMEscan data
KINOMEscan sm3ź-(SfQ°ˣegr3GJɜϕ[vjʧ̣3Ƴ
#JзỌ̃̄[vjјƩě5ğώҐ¥ƈώπʖǬÉ̻ ̶͋ʃпґяϹǏ˞ғžϹɎǮғƋ̋ѥ˵ғƼá©ғ¥ϑΊ»ғƋś̋˪ғɽпƎғƹшƻΉғʘʊɊ

11:20 - 12:10
KI02

Ȱ Ǻ ϴ ˨ Ґ É Ž қ   d    ґ  Ǫя қ ǄČΊ

Molecular docking simulations in the era of network pharmacology
Ґ1ˇ;̓ƞȧφƋƞќƋƞғ2egr{SXf̶͋ʬʥғ3̶̄ґKun-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 conditionŘϗäѿm|]Ї5ф3GJ̇Ř̟̂ʬʥ5ϛʌ
Ґ1 ɜ˩πƋȈ̈ғ2 ʊƋќЛґƋ¨âǊ© 1ғ¥ǎîɾ 2ғÈρţ̼ 2ғŲǒ 2ғљпţƚ 2ғ̋ƨƦ 1ғ̵ҎʱЏ 1

KO11

Anti-inflammatory effect of self-assembling heparin derivatives and their structure-activity
relationshipΤǓͭ΄ĭ|ϬƸÓ5Ȫ˰̛Ö̊0ʥЩ˕Ȍ̪єҐ¹Ƌќπґ

14:10 - 14:50
KO12ǄƮΊғHasan Babazadaғʫ̋û 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 ʊƋı̶̓ґяѐ̵ɵ 1, 2ғ¥ͥǤн 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 kinaseoe[vj5фĭ3GJ˕Ȍĭ5ʥЩYwhҐ1 ˶ʃƋќπғ2 Į˚аƋғ3 SVƋƞґƹʫǏɓĹ 1ғƌшÌˋн 2ғʩǏ̭ʜƚ 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 ͹ͯɳʥЩϛʌ3GJуͧłȈʬʥ5ϛɨҐ˶ʃƋƞƋƞќ̈Ś̓ƞ̶͋пґǄͿFIƚ

15:50- 15:55

ёÉ

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