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SAR News No.27 (Oct. 2014)
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ĭŏ˹ RK-9024466 HCK 3Ƴ!. IC50: 7.7 nM 5јƩ˕ȌN̹!(
Ґū 5ґHCK 0 RK-9024466
5ϏŏÓʥЩN̶̄5ʩDŽH5^”š‚ϛʌ!&K3ź-(ϢϟNυʽЖ̣ПШ3
IC50: 0.43 nM Nȴ, RK-0020449 Nϔď#03Ȟġ!(
RK-449 6̡τ̚ȐΏ̌ʉ5ǡͪΘE&5ǡͪΘNƃʸ%Ā̘ ÉTg3ͅʟ!(ħ
˹s”3.҇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!.JȋȌ҅҆Ȍ̡τ̚5ğπmš`pt
/J
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-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[˜^ʈÅ3GJS˜e“ag]“šw˜^3G+.IC50: 400 nM ͆ǩ
5јƩěN̟ϔ![10]&5ǻ5Ϣϟ0ŏȞ3G+. 1 nM ͆ǩ5јƩě@/ėб!.J[11]
5 Pim1 5јƩěϢϟ3.ʥЩ5ƹ2Ƈĭ3G+.°ʀ!2Ƌ2˕ȌƇĭҐM
FJ activity cliffґNͮ҃!(
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1 æ5˱͎ͧͧ3ƇMJ03G+.ɹƋ/ 200 ç͆ǩ˕Ȍџ!.J
6 ĭŏ˹5*
4 ĭŏ˹6ϏŏÓ5 X ͹ʥЩϛK.J>0O1ʥЩ6ő"/IǼʉ5ĐƚĠŽ3
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D R2 / 0.3-0.5 ͆ǩ/I¼Ŧ5G2ʥЩƇĭ5ƹ2ĭŏ˹ipt3J activity cliff
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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
QYsŠQğπ3JS˜e“ag]“šw˜^Ϣϟ5ǸĞ6ѭǛ3Ƌ
ƋȤώπÇ
ʡ5G3˹щ3G+.јƩě5ȼͨ™ŏȞNυ0ũѨ/J(CÑagt/Ƌ2
chemical space Nȼͨ!ŏȞ#Jĭŏ˹NͰIОB06чϒ/J
́(*5̶͋Ƨ/6
Ʀ̣̊2ȧφҐPALLAS, MUSES, LAILAPSґ5ђ̟00D3ʮ¢Á5ɹý͐ȧφҐFMO-PBSAґ
5ђ̟3DńIͭO/J
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s”NѪƚƭǩ3жŏ%.ˆƤ#J X ͹ʥЩ/6 IJĐ/J
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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!ž@#
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
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0/Ƥщ̣2̪³Ö̊ȒżNÀĢ#J0/J
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-10-
SAR News No.27 (Oct. 2014)
Energy Decomposition AnalysisґĮ˘™Fedorov H3G+.ɂʚK.J [13]
Erlotinib 6
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žǑ6 IFIE 5͏Óňϖĭū/I
ҍΫ/̹#“Z˜u3Ƴ!.Ŏʷź5̪³Ö̊5DZNЈѫΫ5˭/ψ!.J
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-11-
SAR News No.27 (Oct. 2014)
JɝˏJ[12]
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zanamivirҐšŜŒ“•˜d®ґ5̪³Ö̊3.6£ȌSX˜/J“Z˜uĂÓN@0C
JGI6ʬΚпÐ03€’^Œ˜tĐĞ!(ɝŗŪ5QŠyфʷź05̪³Ö̊Nжđ3
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ū 2 6 zanamivir N 4 ,5пĐʥЩ(1)~(4)3ĐĞ!( FMO4-MP2 ϟͯ͘ʎ/J
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-12-
SAR News No.27 (Oct. 2014)
ū 3 FMO ˏ3GJ̪³Ö̊ϛʌ5˖K
Ÿ3υ>1Ϩͪ2ȒżǽHKJ
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FMO 法 を 用 い た 構 造 精 密 化
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˜uпĐ5ʥЩN QM ϟ͘/ˆC̩#0/ͯŏVx”\šɔçDƇĭ!(I͞ǩ IJ
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δͅħ5œ̕2IHID GID HIE 5ɝ“Z˜uͯŏVx”\š 10 kcal/mol ͆ǩƋ
2J0M+(
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ŧA3ū¥5 CAFI 3GJѪδͅħ5Ва̪³Ö̊ϛʌ/6ƔDz2Ɂ÷NǽJ(C36
QM •„”5ʥЩɹжĭȄϒ/+(
-13-
SAR News No.27 (Oct. 2014)
ū 4 FMO пĐʥЩɹжĭϟ͘3GJ}gof˜ˀͧÀĢ˻ȗ5ϥÝ
ҐžқɹжĭʥЩ5ʽЖŸқCAFI 3GJВа̪³Ö̊ϛʌґ
3.2 FMO 超 分 解 能 構 造 解 析
FMO ϟ͘3GJʥЩ͞ƭĭ5D 1 ,5Q‚–šoFMO ЊĐϛΚʥЩϛʌ/J
FMO
ϟ͘Nυ(C36ź32J X ͹ͯɳʥЩĖ̊/J0ĚɂʈÅ/IK@/6
RCSB Protein Data BankҐPDBґ/ĄђK.JʥЩNĖ̊!.Vx”\šϟ͘EʥЩɹжĭ
Nυ+.(
&K3Ƴ!. FMO ЊĐϛΚϛʌ06X ͹ͯɳʥЩϛʌ5‚–ig3̩Ƚ FMO
ϟ͘NĖ̊!.ѪƚƭǩȒż͕Nύơ!ʥЩˆƤ5͞ǩNœž%G0ȧφNȵ!̂
ů̄ĭƞ̶͋ȣ5ʃѓ^”š‚E̽ȡƋƞ5̋¥^”š‚0ąő/̶͋NЫC.J
˺3“
Z˜uŗМ5сǪˆƤ5҇͞ǩĭEa˜€Wš‰š5ĺɻ̀5͞ƭĭˀͧĽƚ5ÐΆˆƤ3є
!.X ͹ͯɳϛʌ5ĐϛΚ 2.0ҟ3.0 ͆ǩ5sšm3Ƴ!.DƦЇ̣3GI҇ĐϛΚ5Ʀ
҃sšmNǽJ50ő͕50бȞ/J0N̨ʧ3!.J
ū 5 Vgt–`˜ŅƫÓ3J“Z˜uŗМ5Ѫƚƭǩ0 FMO ɹжĭʥЩ
-14-
SAR News No.27 (Oct. 2014)
FMO ЊĐϛΚϛʌЯ͆/̊J FMO Ѫƚƭǩ6Đƚ5ĭƞͯŏEĐʢѪƚѩ5ʒГȌ
3ƳȈ!.J
ý5Vgt–`˜ŅƫÓ5“Z˜uŗМ5ɹжĭʥЩ3J FMO Ѫƚƭǩ
NɁ.AJ0Ґū 5ґĭƞͯŏ3ˌ+(ѪƚƭǩĐǕǽHK.IElectron Density Server
ҐEDSґ3̠эK.J X ͹Ѫƚƭǩ0DŏΦ#J
@( MP2 •„”5ɹжĭʥЩH6
17β-estradiol 0ˀͧͯŏ#J Glu 05ѓ3‚–t˜ąɻϙˣKŗМ5Ѫƚƭǩ˭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/5Ѫƚƭǩsšm5ɔëʽЖDЫC.J
ū 6 6 crambin 5҇ĐϛΚʥЩ
Ґ0.48 PDBID: 3NIRґ5*3 ,5a˜€Wš‰šJ Tyr29 3,. X ͹ƭǩ0 FMO
ƭǩNʽЖ!(D5/J[20]
Ŏa˜€Wš‰š3Ƴ!.ϟ͘K( FMO ƭǩNжđ3˝ŏ
#J03G+.Ʀ҃ë3С-.JʦƚMJ
¼ǻ6K3ϥÝєɔNƸā!ĺɻ̀
5ɹжëN˂CJ032J
¿3DFMO ƭǩN̊( 2Fo-Fc G9 Fo-Fc ‰p‚5Ƹā2
13,.̂ůЫC.J
4
おわりに
IFIE NVx”\šȵʧ0!(“Z˜uҔʷźѓ̪³Ö̊5ϥÝ6 FMO ϟ͘5ƠƤ̣2Ė̊ˏ
/J
X ͹ʥЩϛʌ3GJЎѧȒż3Ģ.щƚĭƞ3ź-(Ƥщ̣2̪³Ö̊ȒżNǽ
J0/J(Cğπ̶͋Ώ5ɝ36ɭѭm˜|]Ї0“Z˜u05ąͯɳʥЩńK
(H@$6 FMO ϟ͘Nυ̪³Ö̊ȒżNńǽ!.AJ0ØɝNīC!(Ґup
[˜^ʥЩ3.Dőʦ/Jґ
FMO ϟ͘6¼E̶͋Ƨ5 PC ]’gmJ6ŒwšaQ
5|ka˜/DȤЕ3ϟ͘/J>1БС32+.IĔȃΏ/DØE# GUI Dɕó
K.J
ƋI2ʥЩ͞ƭĭN!2.D›Ω̣2s“˜^k€tN̊(ʥЩ5ĚĎ
̄Nυ+.7ƤỌ̏2Ȓż6ǽHKJ(C&K@/ȔϷ!.2+(̪³Ö̊5чϒȌ
3ʿÀK(IʥЩHǽHKJÃϯ3̄ϲ̣2ϋÀN¡J0/(IŒ“pt
6Ƌ6$/JҐFMO2-MP2/6-31G •„”NȾƒ#Jґ
̂ůIFIE sšm„šg5ʥ͚D
ʠϠ¥/J
GI͞ƭ2̪³Ö̊5ΎưEĐƚsdS˜J6ĭƞłȈŒYwh‹5ϛɨ5(C36G
IƋϕʨ2ϟ͘Ȅϒ02IˑȔ˜ϒ˂KĴ˻/D2I5Ϩͪ2ϛʌ@//J
qš”ɀ+.J
@(¼Ŧ6ϜK2+(ˀś5Ţѷ3,.DĐƚs”EЪͳ˧Ƙ
s”3GJ̶͋ЫO/J[21, 22]
¼ǻ6Ɖ5̶͋ΏũѨNȖ".J“Z˜uŗ
-15-
SAR News No.27 (Oct. 2014)
М5͞ƭʥЩˆƤEłȈ¥ȃ5‚–t˜ĭ˻ȗ21щƚĭƞϟ͘NǒA3˕̊!(Ė̊ˏN̷
͏#J=̶͋NЫC.(0Ύ.J
ϵК
ʃ̶͋5ȾЫ3ĶĠѱ@!(̄ĭƞ̶͋ȣ5ʃѓþЂý̈ˢлijҋĹƆˇDŽ×̈Ĺ
Ɔ̽ȡƋƞ5̋¥ȞĈý̈͏ɐƋƞ5ɿɺ̼Ȇý̈A$>Ȓżͷ̶ʖǬÉ̻5̤ʦ3Ȗϵ
̎!ž@#
@(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) 6ŸϡcStHnT˜–šu/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.
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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 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 /////
Y”‡’˜N̊(ɜϕQ˜u–`˜ŅƫÓȳȪπ5ğώ
ʊĮπ̓Ƌƞ™ƍ̋Ąϕ
はじめに
gr–Su†”˜6&KH5ʥЩ5¥ȃ3Λ˧Ȍ5҇˱ĭˀͧ҅ʙNɻ!.I˺̕
̣2gr–SuŅƫÓ3ͯŏ!̈ÓʬΚNľƭ3ĘǾ!.J
gr–SuÖ̊Nɻ#Jıπ
Ŝ6DZĠ,ƉDž3Ö̊N̹#0HǜǤˋ̨̝̣/Ø̊K.Igr–Su҅ʙN
ŔBD50ѭgr–SuʥЩ5җ,5mS‚3ĐѺKJ
ĚΏ6ŅƫÓ05DZ̖ˀȌ̪
³Ö̊N˾ǽ/JĖ˲JŅƫÓ5зȬȌ0˲/ŢѷNȭ.J
ǻΏ6҇
ŅƫÓзȬȌN˾ǽ/JD55gr–Su†”˜˺ɻ5Ǎ̖҇ˀȌʥЩNʨê#J0
Ѩ!ŅƫÓ05DZͯŏNǽJ06ƫɩ/2Ґū 1ґ
̖҇ˀȌN̹#Ǎ҇ĭŏ
˹0!.Qn‰˜m˜ȶHKJĭŏ˹5ʥЩG9ŏȞ0˲/gr–Suĭŏ˹
5̖ˀȌʥЩ0!.6ɹж062
&5G2¥/˱ͧŔɻ†Tͧ]’gmš5›,0
!.ŇH̳HK.JY”‡’˜3ˑ̨!(
Y”‡’˜6˳ʬĭƞΏN¥ȃ3†Tͧ¥
ȌƚύЍ̝ˏ<5Ȉ̶̦̊͋O32K.( 1)ȟ6Y”‡’˜5ʮúʥЩG9
̖҇ˀȌNğπ<Ė̊#=ẓ̸́2ğπȼͨHıπèύĭŏ˹5ğώ@/ǜǤ̶͋N
ǁђ!.(
/6Y”‡’˜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”‡’˜6²IJѮÓʥЩ5 12 æ5ѱ˲3 2 ,5˱ͧĽƚ0 10 æ5†TͧĽƚÐΆ!(
ʥЩNȴ,ĭŏ˹/Ă.5˱ͧ0†Tͧ3ˀͧĽƚͯŏ!.J(Cƈï6 12 æ5ˀͧ
Ľƚ/ϓMK.I˱ĭˀͧ0ő͕5̖҇ˀȌN̹#Ґū 2ґ
@(ĭƞ̣3ʢC.ƠƤ/
I2 ,5˱ͧĽƚ5ÐΆ5в3GIX”tŒm|’3 ͇5̕ȌÓƜů#J0
Hʮú„˜j˜0DÙHKJ
ɷ3˂ʗłȈE˂ѪƚłȈъǂϜƘ3GJYp‚“˜
^łȈ21ЧǛ5ɻʬŏȞłȈж̊/JÆȔ5˱ͧĽƚE†TͧĽƚž3зỌ̃̄3
ΆɄźNƸā!(ĭŏ˹<ϬƸ#J0ňΚ/J 1)
5G3ŏȞ͞ώG9âƜ@
/ЧǛ5ɻʬĭŏ˹0ő͕3ȥ0/J0Hȟ6Y”‡’˜ıπĭŏ˹5̖
ˀȌ€Pš‰a€WQ0!.Ė̊/J0Ύ(
˺3̖҇ˀȌ0˺ạ̏2͏ÓʥЩNɻ#
Jgr–Su҅ʙ5›пNY”‡’˜/ΆɄJ0/ѭgr–SuʥЩNɻ#Jĭŏ˹3
DZ̖ˀȌ̪³Ö̊NÀ¡!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–`˜6AR <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 5ͯŏʦǬ6ąͯɳʥЩHɨH02
+.J 4)
DHT 5Y”‡w”ź6 AR 5 Arg752 G9 Gln711 0ˀфź6 Asn705 G9 Thr877
0ˀͧͯŏNdzȞ!.Igr–Su҅ʙ6KHˀͧͯŏȌƣΚź5͌ѓсΆ0 AR 5̖ˀ
Ȍˆ_pt05̖ˀȌ̪³Ö̊3є¡!.JҐū 3ґ
AR 6ʗĉŅƫÓ/I“Z˜uͯŏ
Ѵŷ3̈ÓĉQ˜u–`˜ͯŏ!(ǻ͇5aQ]o„šmš0ДċŧƚϏŏÓNdzȞ#
J0/Q˜u–`˜Ö̊N̟Ʌ#J
5ɮAR 5 12 ̨̔5<“p]gҐH12ґQbwg
tсǪ32J0aQ]o„šmšͯŏ!ДċàЫKJ
›ɝ“Z˜u5ͯŏ3GI
H12 QbwgtсǪN0K2Žŏ6aQ]o„šmšͯŏ/$ŅƫÓ5˕ȌĭȨĘ
K&KH6Q˜mbwgt0!.ʬΚ#JҐū 3ґ
Сǟ̻É5҇ҏĭ0ѽ̈˕5ʯ͜ĭ3ËĚ͏Ο̞5·Ȑ̀0ʶ¶̀5ȋˬ2ƃĢŢѷ
02+.JĚ͏Ο̞5>0O16Q˜u–`˜ÜƜ̣3ƃʸ#J(C AR Q˜mbwgt
&5ˋ̝3Ǥ̊HK.J 5)
Ě͏Ο̞ˋ̝π/J flutamide 6&KΤБD AR 3ͯŏ
#JÓĉ/˕ȌÁϵ˹/J hydroxyflutamide 3ƇɄK(5* AR 3DZĠ3ͯŏ#J
&
/ɜϕ AR Q˜mbwgtNğώ#=€Uw”Y”‡’˜҅ʙN AR Q˜mbwgt5
€Pš‰a€WQg[Ž€Wš”u0ϕƤ!„˜j˜̆žG9Y”‡’˜˱ͧžΆɄźNȼ
ͨ!(
ĭŏ˹5Y”‡’˜ AR 5̖ˀȌˆ_pt0DZͯŏ!,Y”‡’˜5͏Ọ́
Ǎ҇3GI H12 QbwgtсǪ32J0NјƩ/K7KHĭŏ˹DZĠ2 AR Q
˜mbwgt0!.Ö̊#J0NʀǺ!(
&5ͯʎhydroxyflutamide GIDDZĠ2 AR ͯ
ŏΚG9 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[˜^eŠ•še‘˜HBA341 5eQyź Gln711 G9 Arg752
0ˀͧͯŏNdzȞ!.J0̹şK(Ґū 5ґ
@(}–u[eŒo”ź6 Thr877 G
9 Asn705 5ïюY”‡w”ź0ˀͧͯŏNdzȞ!.IDHT 0 AR 5ͯŏʦǬ0>?őʦ5
ͯʎǽHK(
3DMH$DHT 0̕2I AR Q˜mbwgt0!.ʬΚ!(06ѭ
Ǜ3ΧŘ˜Y”‡’˜AR 5 H12 QbwgtсǪNńJ0Nƕ.J0ΎHK
(
up[˜^5ͯʎHH12 5ʥȞQŠyф/J Met895Ґū 5, ˜]ґ5ʷź BA341
5Y”‡’˜̆3ȽС!.IY”‡’˜5Ǎ҇ H12 NQbwgtсǪHȹѝ!(
0Q˜mbwgt˕Ȍ3ͯ9,(0ΎHKJ
,@IBA341 5Y”‡’˜̆6gr
–Su҅ʙ5̖҇ˀȌ5ʹȴG9͏Ọ́Ǎ҇3GJQ˜mbwgt˕Ȍ5̟̂5җ,5
ǸĞN˨".J0ɨH02+(
図 5 B A 3 4 1 と A R の ド ッ キ ン グ シ ミ ュ レ ー シ ョ ン （ 立 体 視 図 ） BA341 誘 導 体 の AR ア ン タ ゴ ニ ス ト 活 性
AR Q˜mbwgt˕Ȍ5̟̂36AR 5 H12 QbwgtсǪNʹȴ/22JG2
“Z˜uʥЩчϒ/J0HH12 Сñ3ÐΆ#J BA341 5}u–[eŒo”źпÐ5
ʥЩäѿNϦA(
@(AR 5 Asn705 G9 Thr877 05ˀͧͯŏNΎȚ3āKˀͧͯŏȌ
ƣΚźNɻ#J 1a-1h NŏȞ!ΆɄź5ǷѰ3,.ʠϠ!(Ґψ 1ґ
ˀфźNɻ#JϬƸÓ
1a-1d 6BA341 GIίǝ AR <5ͯŏ6џ!(D55҇ͯŏΚN̹!(
›ɝ_t˜Ϭ
ƸÓ 1f1g G9Vˆ[eϬƸÓ 1h /6 AR 3Ƴ#JͯŏΚ6Ѹκ3џ!(
5ͯʎ6
BA341 5}u–[eŒo”ź5пĐ3ˀͧͯŏuvš5Ɯůчϒ/J0N̹!.I
up[˜^eŠ•še‘˜H°ˣK(̪³Ö̊ҐAsn705 5Y”‡w”ź05ˀͧͯŏґ
0D›Φ#J
AR 5Дċ˕ȌĭϦ҃/6}u–[eϬƸÓG9Y”‡w”ϬƸÓ$K3
.DƸā!(ΆɄźƋ2J0˕Ȍ5џϔHK(Ґ}u–[eϬƸÓқBA341 > 1a
> 1b2 ΆɄ}u–[eϬƸÓқ1c > 1dY”‡w”ϬƸÓқ1e > 1f > 1gґ
@(Q”s}u
ϬƸÓ 1e BA341 0>?ő"•„”5 AR ͯŏΚG9 AR Q˜mbwgt˕ȌN̹!(̄
̌6ɨ̷/62Y”‡’˜5ѪƚŕǭȌ3GI˕Ȍĭ!(Y”‡w”źˀś!.J
021ΎHKJ
BA341 5eQyź6ˀͧͯŏQ]i‚mš0!. Arg752 0 Gln711 0̪
³Ö̊#J
&/ĭŏ˹ 1c 5eQyźNGI”SgƁźȌ5҇Qio”ź<ƇɄ!(0
LAR 3Ƴ#JͯŏΚ6ʹȴ!(D55Дċ˕ȌĭΚ6Ѹκ3џ!(
ˀͧͯŏ5ɝœ5
ƇĭEQio”ź5Œo”пĐ3GJ͏ÓѣƩ21ĭŏ˹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˜[„še‘˜!(
&5ǻDCC /Ď
̄!дȃĐѧ!(ž˞3Ŕ@KJ AR ͯŏ[3H]-DHT 5ɍƶ˕ȌNˣƤ!(
Binding affinity 6DHT 5 AR-LBD <5ͯ
ŏN 100 0!(ɮ5̪Ƴͯŏ̀0!.͘ďK(
b
NIH3T3 ͪΘ3 hAR ̟̂‚’gŠu0 AR Ȉ͗сēNŔB Luciferase ̟̂‚’gŠuNͭAОADHT G9Ϧ҃ĭŏ
˹NĢ5% CO2 ƜůŸ37 oC / 24 ɮѓS˜[„še‘˜!(
&5ǻ”e€U’šj˕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 3GIĚ͏Ο̞ƃʸ™ȑĭ#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 3DQ˜mbwgt˕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–[eŒo”
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–[eŒo”źŗМ3͏Ọ́3Ǎ҇ïюNƸā#J00!(
ĚУ!(G35
пÐŗМ/6Œo”ź5G2ΆɄźϣƫKJ0HŒo•˜N½!.€Uw”ïюN
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 “˜Yš0!. O E S Nɻ#JϬƸÓ 3a-3d G9 4a-4d 6bicalutamide GIÑ AR ͯŏ
ΚN̹!(QitQŠuźNɻ#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 5“˜YšпÐ̕2
J0EAR wildtype T877A mutant 5в3Љŧ#J0ΎHKJ
ͳ.bicalutamide
0ő" SO2 “˜YšNɻ#Jĭŏ˹ 5a G9 5b 5˕ȌNϥÝ!(0Lbicalutamide GID
Ñ AR ͯŏΚN̹!(
˺3QitQŠuźNɻ#J 5b 5 AR ͯŏΚ6Ѹκ3џ!(
H3ΧŘ˜035a G9 5b ą3 LNCaP ͪΘ3Ƴ#JƃʸȨĘĥʎ6ϔHK2+(
Y”‡’˜Ŕɻĭŏ˹/6Y”‡’˜̆5̖҇ˀȌ̪³Ö̊ö(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 3Dɻĥ2ȪQ˜u–`˜5ђ̟ɤȋ3˂
CHK.J 9)
ĭŏ˹ 3b G9 4b 6bicalutamide 5ʥЩNź3sdS˜!.I bicalutamide
0Î(G2ĥʎN̹#0ΎHKJBWS 5Ľŧ02J AR 5 Trp741 5Ƈ̕3Ƴ!Y”‡
’˜̆žȤʬΚ#K7 BWS 3Dɻĥ/L
$K3%GAR 5QŠyфƇ̕Nʿ3
!2HQ˜mbwgtNğώ!ͳJ56Smo+ő˴/J
&/ȟ6H12
Qbwgt€Wš‹NńH2G͏Ọ́3Ǎ҇Y”‡’˜/ H12 G9&5ŗМN̩
-22-
SAR News No.27 (Oct. 2014)
ȽјƩ#JG2ĭŏ˹NΎʚ!(
#2M*AR 0 BA341 5eQyź5ˀͧͯŏN^“i
–š”ʥЩ/ʨê#J03GI€Pš‰a€WQ/J€Uw”Y”‡’˜ʥЩGI H12
3ȽС!(ɜ(2mS‚5 AR €”Q˜mbwgtğώ/J0ʀǺ!(Ґū 6ґ10)
@(
^“i–š”ź36ˀͧͯŏňΚ2пÐǢ,Ɯů#J(CeQyźNɻ#Jĭŏ˹GI
DDZ AR 3ͯŏ#J0ΎHKJ
/6^“i–š”ϬƸÓ3Ƴ!.ǽHK(ͯʎ5›
пNͫ½#J
ŏȞ!(^“i–š”ϬƸÓ 6a-6c 6$KD AR 3ͯŏ!(fXš”ʥЩ
NQit˜/âϸ!(ϬƸÓ 6d 6 AR 3ͯŏ!2+(Ґψ 3ґ
K6ĭŏ˹5^“i–š
”ź AR 5QŠyфʷź0̪³Ö̊!.JϤȱ/Iʃĭŏ˹sdS˜5ƔDzȌNɋȴ#
JʢC.чϒ2ͯʎ/J
T877A Ƈ̕ AR N̟̂!.J LNCaP ͪΘ3Ƴ#JƃʸȨĘΚ6
Y”‡’˜ž3ΆɄź52 6c /Dǰ2HϪCHK(
@(&5˕Ȍ5DZ6Y”‡’
˜̆HďJïю5я3ÜƜ!Ґ6a > 6b > 6cґ6a 6 bicalutamide 0>?ő͕5˕ȌN̹!(
ʃͯʎ6Y”‡’˜̆ H12 N̩Ƚ̣3јƩ!.J0N̹ş!.J
KH5ĭŏ˹
6 bicalutamide 0Ƌ̕2JʥЩNɻ!.I BWS 3Ƴ!.Dɻĥ0ΎHK¼ǻ5ϥÝ
ͯʎ3ʀǺ!(
AR Q˜mbwgt3GJĚ͏Ο̞ˋ̝/6͖ͭ΄/5 AR 5Ö̊ȨĘKJ03GJ
͖щ5џŢѷ02J0DJ
Ȫ AR π5ĜÖ̊5Еˡ36ȪQ˜u–`˜Ö̊0Ȫm
˜|]őĭÖ̊5Đѧ ňʭ/Iͭ΄зỌ̃̄Q˜u–`˜ŅƫÓĘǾπҐSARMґD@(
̦O3̶͋2K.J
Ϩͪ6У=2ȟ6Y”‡’˜NĖ̊!( SARM 5ȼͨD
Ьυ!.IAR |šeŽ”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/6ɜϕ̖ˀȌ€Pš‰a€WQ3̨̰!(ğπ̶͋5¥5AR Q˜mbwgt5ğ
ώ3,.ͫ½!(
ɹС/6¤υ!.ЫC.JY”‡’˜5˹̄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 š ’ ‹ 2014 ђ ô ż Ŗ
ũѨĭ#JıπŜђ̟5̂˻0Ʒʉ
ʥЩ˕Ȍ€Wš’‹ 2014
ƦυƗŞя ҇ʁб­
ʥЩ˕Ȍ€Wš’‹ 2014 66 ɺ 27 ɡ(ъ)ƋїƋƞa˜„˜e‘˜i˜mš3.
ũѨĭ
#JıπŜђ̟5̂˻0Ʒʉ0ѷ!.ђôK(
ɜϕıπŜ5ђ̟6ǟNФʻ3ũѨ32+..J
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žǔK..ђ̟3Dz(+.ÔH5Ƅ3;,JıπŜʷK.5/JHμ
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˺3Сǟ/6QYsŠQ/ź̸̶͋Nυ&5ź̧ȧφNώπÇʡȈ̊#J0ūǬ
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D*LOQYsŠQğπEώπÇʡ3Jź̸̶͋Ǣ,
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ҖҕQYsŠ̟ğπƦ̂5(C5ɋɆxpt—š]5ńIͭA
҇ƚ ȂҐ˼͏υɎˏ» ıπź̶̧͋ȣґ
җҕѻAHK2˷ǙȖʑ̛ҐNTDsґ̶͋<5ńIͭA
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ҘҕUnstructured/Structured Interaction Nʧ̣3!(ğπ
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ҙҕFINDSҟrš‰ĄĩųıπŜ̶͋ešh̟Ⱥ5ϦA
ʋʃ ǯ̈ҐƁшΊώπʖǬÉ̻ґ
Қҕ|x”sRgYpe‘˜
ıπź̶̧͋ȣ5҇ƚȂý̈36ɡʃ5QYsŠQ5ȴ,ź̸̶͋ĠNğπ3ͯ9,J=
ƖCHK(ğπɋɆxpt—š]3,.˺3ıπź̶̧͋ȣ3ϢΆK(ğπɋɆȠ
̓Ƨ3Jğπv~0ğπQšYS5²,5±ʡNϨ!ϛϯ!.ѱ(
ğπ
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D(H#/L06̗Õű620ȊMKJ
Qgr’gώπʖǬÉ̻5ɜΉб­ý̈36§0!.̟ǁЦžŭ5ÑȣǽΏǃN¥ȃ3νǫ
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ѱ(
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SAR News No.27 (Oct. 2014)
PRISM BioLab ʖǬÉ̻5ƹЏǮυý̈36̂ů@/>0O1ȞġÙ52ͪΘĉς̡Їѓ
̪³Ö̊˺3 Structured-Unstructured ̪³Ö̊NĘǾ#J03GIıπŜђ̟3΃Jȧ
ˏ3,.ϛϯ!.ѱ(
ŭĉ/6ƺɔ5{SX„˜oŽšÇʡ/Iʶ5Ϲ3ʐ
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Ɯů/J06ϲNǺ(2
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21ƺ20DɗЁΏ6ňΚ/L0DΎ2+()3ȔŘ/҄̕5ȉNȴ+.
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ý̈3ƦυƗŞяNǭŅѱ@!(
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-26-
SAR News No.27 (Oct. 2014)
///// Activities /////
ҜÉŖҝ
͒ 42 Ŧ ʥ Щ ˕ Ȍ ̪ є e ˜ ˆ f T ‹
ɡɮқǞȞ 26 ǟ 11 ɺ 13 ɡҐʁґ™14 ɡҐъґ
ÉŽқ@D0ʞрȃ‚’dҐ860-0047 ˶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 † š ” ґ Ǫя қ ƨʃ̀›
KO01
Prediction of three-dimensional structures and structural flexibilities of wild-type and mutant
CYP1A2 by molecular dynamics simulations
ĐƚħĠƞeŠ•še‘˜N̊(ш̈ų™Ƈ̕ų 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(oX“nf˜5 CYP2D6 3GJÁϵЯ͆5ѭ̣ͮ҃ϛʌҐIґ
ҐȀljƋќπґ͓Ľÿęғ҂ljǵғŐ̋бϼғ¥҂Ư
KO03
Development of in silico prediction model on environmental fate of chemical substances
̆Ƃ¥3Jĭƞ˹Ї5ĢˀĐϛȌ°ˣegr‹5ʥ͚
Ґ1 їƋќπғ2 їƋǿ̈˹̶͋̚ȣґƟʘ̅ 1ғdžʃɯĈ 1ғƨNjƋЂ 1ғ
ǏŸ̄ɡ» 1, 2ғ҇ʁб­ 1, 2
11:15 - 12:05
KI01
Ȱ Ǻ ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” ґ Ǫя қ ˁ̋ƻ­
Three-dimensional protein structure and dynamics in living cells
̈(ͪΘĉ/5ς̡Ї5͏ÓʥЩ0nSvŠ]g
ҐҁрƋƞʊ¹ ̄ǐƞ̶͋̓ґ˅ϹьĆ
13:30 - 14:30
KO04
› Ω ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” ґ Ǫя қ҇ʁб­
Structure-activity relationship of ecdysone agonists bearing imidazole skeleton
SŠnlš”͠Ν̥†”˜Qbwgt5ʥЩ˕Ȍ̪є
Ґ¹ƋќЛґʩµƋ˓ғķˈ͡ғ̵ſijеғ¥ǏƓ͂ғƨǏȎ
KO05
3D-QSAR study of neonicotinoid insecticides having a substituent on the 5 position of the
imidazolidine ring
SŠnl“f˜̆ 5 Ð3͇5ΆɄźNɻ#JSŠn]–‚“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
ˆgmšipe‘˜ ҐÉŽқ†—SVґ
14:40 - 15:40 Əɔ̟̔ψ
15:40 - 16:40 ðɔ̟̔ψ
17:00 - 18:00
KS01
˺ ĕ ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” ґ Ǫя қ ¼µЙƚ
How to predict the diversity of drug-induced liver injury?
π˹ȌΔѣƩ5ƉʦȌ<5ƳȈ0°ˣ
ҐŒŇǀƋƞƋƞќıƞ̶͋̓͠ґʩµʺ
18:30 –
ȜϘÉ ҐÉŽқ†r”wšXšmw˶ʃґ
-28-
SAR News No.27 (Oct. 2014)
ˆ g m š 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 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“Šfy˜ϬƸÓ5ğώ
Ґ̶̓ώπґдρĦ½ғˊŏîƍнғ˗шʲōғƌш¢ˋғ˫̋ŰИғžƼ͡ƚғ
҇ʫÌɨғŮ̋џғ¯µ˦ªғˁ̋ƻ­
KP03
Analysis of inter-molecular interaction between kinase domains required for transphosphorylation of receptor tyrosine kinase
јƩěΐȌƇ̕Óo–e˜[všj0јƩě05̪³Ö̊5ϛʌ
Ґ1 ˶ʃƋπғ2 Į˚аƋғ3 SVš”Ƌƞґ¡Ǫ҉ɚ 1ғƹʫǏɓĹ 1ғʞdžǮȆ 1ғ
ƌшÌˋн 2ғʩǏ̭ʜƚ 2ғJoseph Schressinger3ғ͈ŴčǴ 2
KP04
Identification of ligands of DJ-1 with biophysical screening
˹̄ĭƞ̣ȤˏN̊( DJ-1 ƹĐƚĭŏ˹g]“šw˜^
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
}tG9c”Y”‡[e”Vgr’šj 2 уͧ5 1 QŠyфƇ̕3GJźЇͯŏп
Ð5ʥЩƇĭ0źЇϪϷȌ5̪в
Ґ1 ˶ʃƋπғ2 Qg~X€Pš‰ғ3 ̉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€’^Œ˜tˏN̊(ĭƞ˹Ї5ҊʼȌ°ˣқ˃̊|’Œšm0æĕ|’Œš
m
ҐϺʫȧ̓Ƌќǐґ˅žό²ғ҇ʫ̌ѥ
KP07
Study on binding of sodium phenylbutyrate to human serum albumin
€Uw”тфvt“T‹5τ˞Q”Š˜ͯŏ˺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˫ɜ›н 1ғŏ̋˙ɨ 2ғǤшä› 1
KP09
Partial similarity analyses of ligand-binding sites on proteins
m˜|]Ї¥5“Z˜uͯŏпÐ5пĐѺÎȌϛʌ
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(C5“Z˜u„šg{šoŽ”g]“šw˜^Ȥˏ5ђ̟Ґ&
5 4ґқʥЩ€R˜Zš‚“˜t5ɌΪ
ҐĮцƋπґоō¨ȏғϑ͐έǴ
KP12
The construction of a pairwise database of ChEMBL ligands with 3D superimposition and
structural transformation application
ChEMBL N̊( 3D ч4ŏM%sšm„šgʥ͚0ʥЩƇɄ<5Ȉ̊
Ґ̶̄ CLSTґʫʃțɨғǠ̲ғʃѓþЂ
KP13
Comparative analysis of intermolecular interaction of influenza neuraminidase with sialic acid
substrate and its analog inhibitors
ϜƘłȈʬʥ3ź-(S˜€”V˜d™yS’Šwnšj0eQ”фϬƸÓ05̪
³Ö̊ϛʌ
ҐȀljƋќπґά̋Ѥ̠ғŐ̋бϼғ¥҂Ư
KP14
LERE-QSAR analysis of papain and trypsin hydrolysis of a series of substituted phenyl
hippurate esters
҂ƽф€Uw”Vgr”5egrS˜0i“˜‚–rQšj5ĢˀĐϛłȈ5Đƚ̓
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 0Q–€Uw”y”gmo˜҅ʙNȴ,ĭŏ˹
05ϏŏÓ5͞ƭ̪³Ö̊ϛʌ
ҐȀljƋќπґʍɓ¨ғшΜѬғŐ̋бϼғ¥҂Ư
KP16
Use of expanded perception of protein-ligand interactions as a fingerptint
Ϩͪ2ѭͯŏ̪³Ö̊ϪϷ5 Fingerprint 0!.5Ė̊
Ґ1 Q]i”“gʖǬÉ̻ғ2BIOVIA 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 e•šsR˜ZšʖǬÉ̻ғ2 їƋ JST ERATO ΛЇ˕ȌʥЩ‚–fU]tғ3 їƋ
ќ̄ғ4 їƋź̸̄ƞ‚–fU]t̶͋i˜mšґǔĽŃ 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-({”všj-{”gmšϏŏÓ5ͯŏΚϥÝ
ҐĮцƋπґ˞̋˒΢ғnjȞΉғ͑̋-ȆҌ̭̌ƚ
-30-
SAR News No.27 (Oct. 2014)
KP20
Protein active site comparison with SiteHopper: Phylogeny to polypharmacology
Ґ1 Xš‚˜QS™fŽ|˜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 ŅƫÓQ˜mbwgt5̶͋ -†–fšs”N̊(–“y˜ϬƸ
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˜|]ЇҔиÊƚсēoš€ϛʌegr‹5ђ̟
ҐϺʫȧ̓ƋќǐґDŽʃ˪źғĢρĹɨ
KP23
Mechanism for producing structure and functional variation of short chain dehydrogenase/
reductase (SDR) family proteins
Short chain dehydrogenase/ reductaseҐSDRґ€PŠ“ς̡Ї5ƉʦȌ˾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#J҇ϘśȌ“Z˜u 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{šoŽ”g]“šw˜^sšmNĖ̊!(X€mš`ptȼͨ
ҐQg~X€Pš‰ʖǬÉ̻ґŭʃºғdžʃɒ©
KP26
Development of the structural feature analysis system for molecules based on the threedimensional neighborhood information
ʮúСñȒż3ź-Đƚ5ʥЩ˺ȁϛʌegr‹5ђ̟
ҐϺʫȧ̓ƋќǐґÒЃĦŝғĢρĹɨ
KP27
Relation between eigenvector of molecular matrix and atomic environment of molecule
Đƚυē5Ŭɻ„]t”0Đƚĉƾȣ̆Ƃ5̪є
ҐϺʫȧ̓Ƌќǐґʞº̭ғ҇ʫ̌ѥ
KP28
Development of integrated drug database and analysis of rhabdomyolysis by ATC codes
ıπŜͱŏsšm„šg5ÖȞ0 ATC ašu3GJʩ͖ͤσϛ̛5ϛʌ
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 š m „ š g CUES: Convert it Unique and Elegant
Substructure 5ђ̟0Ȉ̊
Ґ1 Ǘ»€Pš‰ғ2 ̶̄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 † š ” 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
“Z˜uҔm˜|]Ї5ϏŏÓdzȞ3JĐɑĠ̪³Ö̊5ʠϠ: LERE-QSAR ϛʌ
3Jͯŏ̪³Ö̊Vx”\šѲ5Ƥщ̣ϥÝ
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–[c‹фϬƸÓ5 LIE ˏ3źϛʌғLERE-QSAR ϛʌ0ʠϤ
ҐȀljƋќπґшŸΨғˮшͶмғLjùÖғŐ̋бϼғ¥҂Ư
KO09
Novel protein structure alignment method based on the residue-residue interaction
ʷźѓ̪³Ö̊3ź-ɜ(2m˜|]ЇʥЩQ’SŒ˜tˏ5ђ̟
ҐĮцƋπґƲǘ˿ϡғ͑̋ҔȆҌ̭̌ƚ
10:30 - 11:10
KR01
Ü Ѷ ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” 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 sšm3ź-(„SfQ˜°ˣegr‹3GJɜϕ[všjʧ̣3Ƴ
#JзỌ̃̄[všjјƩě5ğώ
Ґ¥ƈώπʖǬÉ̻ ̶͋ʃпґяϹǏ˞ғžϹɎǮғƋ̋ѥ˵ғƼá©ғ
¥ϑΊ»ғƋś̋˪ғɽп›ƎғƹшƻΉғʘʊɊ
11:20 - 12:10
KI02
Ȱ Ǻ ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” ґ Ǫя қ DŽŸČΊ
Molecular docking simulations in the era of network pharmacology
Ґ1ˇ;̓ƞȧφƋƞќƋƞғ2egr‹™{SX–fš̶͋ʬʥғ3̶̄ґKun-Yi Hsin1ғ
Samik Ghosh2, 3ғĮшƢɨ1-3 13:30 - 14:10
KO10
› Ω ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” 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¥ǎî›ɾ 2ғÈρţ̼ 2ғŲǒ 2ғ
љпţƚ 2ғ̋ƨƦ 1ғ̵ҎʱЏ 1
KO11
Anti-inflammatory effect of self-assembling heparin derivatives and their structure-activity
relationship
ΤǓͭ΄ĭƒ|“˜ϬƸÓ5Ȫ˰̛Ö̊0ʥЩ˕Ȍ̪є
Ґ¹ƋќπґDŽŸƮΊғHasan Babazadaғʫ̋û
14:10 - 14:50
KO12
› Ω ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” 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
¥ͥ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 kinase
o–e˜[všj5“˜фĭ3GJ˕Ȍĭ5ʥЩŒYwh‹
Ґ1 ˶ʃƋќπғ2 Į˚аƋғ3 SVš”ƋƞґƹʫǏɓĹ 1ғƌшÌˋн 2ғ
ʩǏ̭ʜƚ 2ғʞdžǮȆ 1ғJoseph Schressinger3ғ͈ŴčǴ 2
15:00- 15:50
KI03
Ȱ Ǻ ϴ ˨ Ґ É Ž қ ‚ ’ d † š ” 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 ǞȞ 26 ǟ 10 ɺ 16 ɡ
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