SAR News No.27

ʥЩ˕Ȍ̪єпÉwgm <16 October, 2014>
SAR News No.27
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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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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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SAR News No.27 (Oct. 2014)
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жĭϟ͘!FMO 5 IFIEҐ^tѓ̪³Ö̊Vx\ґ5ŏϟë0 MM-PBSA 5 PBSA
ѲпĐNŏM%(ëNϟ͘!log IC50 05̪єNϔ(0LR2=0.92 0̪҇єN̹!(
Ґϲɗȩ͉˦ó¥ґ
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X ͹ʥЩ&5
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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˹Â
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
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DЫO/J[5-8]
FMO ˏ3є!.6ɹС5ɡʃĭƞÉ5ȒżĭƞпÉϩ3Ŧ3ˢ+.˺
ѦK.J0HDˑ̨ǩJ[9]
FMO ˏ6m|]ЇNQyфʷźĸÐ215^t3ĐĞ!ŗМ5^
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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
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ĐĞ3Ѣ!.͞ǩʠϤK.J56sp3 ˱ͧN Bond Detached
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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#
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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+(
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§ȞĐ0!.Zu0̪³Ö̊#JʷźƉɔƜů!.JҐū 1ґ
ū 1 EGFR oe[vj0 erlotinib 05̪³Ö̊ϛʌ
Ǒ6 IFIE 5͏Óňϖĭū/I
ҍΫ/̹#Zu3Ƴ!.Ŏʷź5̪³Ö̊5ǱNЈѫΫ5˭/ψ!.J
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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,
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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
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˻ȗ5®KNύʱ!ĭŏ˹0!.5ȌЇNɇ202ϛʌ#J0/J[12]
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ū 2 SVd NA 0 zanamivir 5 FMO4-IFIE ϛʌ
Ϋ5ψ̹6ū 1 0őʦҐĸÐ6
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2.3 相互作用解析の流れ
IFIE g5̪³Ö̊ϛʌ36¿3D VISCANA [15]215ĭŏ˹]gm^ȤˏD
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1 ,
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/^tĐĞ5͞ǩDoUp]#J
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PIEDA 3G+. IFIE 5Vx\ȞĐNĐϛ!̪³Ö̊5ȌЇN̄ϛ#J
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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. Fragment molecular orbital method: an
approximate 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. and
Okazaki, 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 of
bisphosphates 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 7.0BioStation Viewer 16.0) 6ϡcStHnTu/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. and
Nakano, T. Three- and four-body corrected fragment molecular orbital calculations with a novel
subdividing 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.
-16-
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 the
fragment 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.
-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(˭ǩÜƜɶ͹H 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. 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 androgen
antagonists 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 prostate
cancer 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, 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#J03GIıπŜђ̟3΃Jȧ
ˏ3,.ϛϯ!.ѱ(
ŭĉ/6ƺɔ5{SXoÇʡ/Iʶ5Ϲ3ʐ
Jʫ0!.ʀǺKJEɠ3чϒ2ȞʎN,,J¼ǻ5ıπŜђ̟3ʭ%2
Ɯů/J06ϲNǺ(2
˺3΂ʹĭ!(ΔΡ215ͭ΄5Ν΂ʹĭ0ˋ̝ˏ
21ƺ20DɗЁΏ6ňΚ/L0DΎ2+()3ȔŘ/҄̕5ȉNȴ+.
Í0/(
ƁшΊώπʖǬÉ̻5ʋʃǯ̈ý̈36ƁшΊώπN¥ȃ0!(XSye5
ϦA5,/JFINDSҟrĄĩųıπŜ̶͋eh̟Ⱥҟ3,.Ąĩ3GIQY
sQ5ğπ3΃Jź̸̶͋N̟Ⱥ!ΣǥϦ҃<΃JϦA3,.Ϩ!ϛϯ!.ѱ
(
5fU]t6̂ů/6ŭѢĭЫASHIONOGI Science Program 0!.̂ů 11
Yŭ/ƦɞK.J050/J
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ʎ6»ѺĂÓ¸Ņ#J=/L
5ǻϴ˨ѱ(ý̈ɝ3ʷ+.ѱ(|xsRgYpeɻȔΊ/+(0N
ϡ!.472H2Ϩͪ6̫̓%.ѱ˳̺Nϣ!ѱ(
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IΦ!@!.˜Ȗϵ̎!@#
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̋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 ̉ͷ̶ґµǏ×© 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˕Ȍ̪єҐƁшΊώπҐʖґґʕĽƐ͸ƚғɥîƍнғ̽̋˒ǴғѼˁό©ғ¯ǄЂ©ғ
̍ə˙Ǡ
KP22
Development of the protein-gene sequence motif analysis system based on the codon reduced
representation
au΁͢ψ̂3ź-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)
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SAR News No.27

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