05 2; 歯視 Organic Cation Transporter 1 (hOCT1) 作梏載三 鹿始叱詞杢倫H搾沢哨柊侍残質治志侍嗣仕搾蘓暘埼 3D-QSAR ∑勿膵彖疾や∭ 禁柘虫歸漉鍮饑彖超漉単㎲饗漉樂地譴弾漉倫｠⒊躬漉煥菲篤滝 ォウ 瘼疿瘜 やH視汐叱施滋質獅質昨やH搾歴離疾返漑疾追 ▲疾薛牙作門濁菜漉やH追▲雙㊌埼谷策やH搾鉄敏 岬絆桟】暘載三臍さ鷺嗔攷崎催三腰SLC22A 侍残爾 鹿質作榾載三 Organic Cation Transporter 1 (OCT1) 昨漉短作わg作才犀三鏨㌣士私四叱搾歴離作門濁菜漉 嫗㈻桟わ禁ヤ敏作掠晒㎲札痙房桟霄財菜咲最三 [1] 腰 OCT1昨敏嗔磔搾士私四叱冴犀崎鷺災漉弋嗔磔搾士私 四叱磔やH鷺碕煥⑧鷺杢倫H桟嫗㈻埼菜咲をか載三 砦埼栽返採堺咲最三栽漉材搾イ鉄└『皐嫗㈻をか㌣ └搾レ禁作榊最咲昨撮冴躬皿採作鷺堺咲最鷺最腰材 搾財殺漉 OCT1搾鹿始叱詞0倫校溺作門載三鮫晒レ禁 鷺Pよ昨漉ⅲ惚搾杢倫H搾鉄敏岬絆桟Pよ載三財殺 搾鏨ブ鷺筅寃作鷺晒漉やHó4桟a綽菜財返攷スゝ 作才最咲鉄敏岬絆ɔ作鏨戊鷺やH桟某瞥載三財殺搾 臍さ鷺さ嗔作鷺三埼a宰皿傘三腰 材砦崎漉畚ŠW曄崎麻o菜財 Ligand-Based Drug Design 胯叛 ∑イ鉄噴燒 よ 隸字鴫屍汐璽 CAMDAS [2] 漉臍咋倫惨剤胯叛 SUPERPOSE [3] 漉 CoMFA [4] ∭ 桟ブ最咲漉鹿始叱詞搾0倫噴燒才鮫策 沢哨柊侍残質治志侍嗣仕桟】暘菜漉材傘作嫗肴最財 3D-QSAR 磁至式桟└3菜財腰 撮財漉S. H. Wright 皿作鮫晒歯視 OCT1 作梏菜咲 揆朖㌕磔桟薩榊鹿始叱詞作門菜咲 Catalyst 採皿蘓 暘斎傘財侍残質治志侍嗣仕作嫗肴歳漉 Cerius 2 桟ブ最 咲 Descriptor-Based QSAR よ隸栽〒惨傘漉材搾嫡㎦ 勝栽a柞斎傘咲最三 [5] 腰材砦崎漉痞皿搾 QSAR 磁至 式埼鑢ŠW崎癆皿傘財 3D-QSAR 磁至式桟屛Ç疾鶚 ワ菜財腰 [email protected] オウ 赭叛 竨䇮种礛窂篔玫㎟返攷岬堀斟䏰 MD脤叛瞟戊ブ疷 痠筁磕箐稛杢倫H瘨イ鉄噴燒よ隸 歯視 OCT1 崎ó4斎傘三緑鹿始叱詞杢倫H作梏 菜咲漉畚ŠW曄崎麻o菜財字鴫屍汐璽 CAMDAS 桟 ブ最咲イ鉄噴燒よ隸桟〒堺財腰 CAMDAS 崎昨漉撮際返攷搾椿籟搾補鐵└『桟ブ 最咲玫㎟返攷岬堀斟ゝ五桟〒最漉瞥I菜財イ鉄噴燒 桟滝暘搾辣脈脈翆崎指叱字鹿叱屍載三腰哨作緑イ鉄 噴燒作梏菜咲史諮式姿質黻棊杢桟〒最漉莎暘菜財宙 倧み桟屛Ç載三砦埼作鮫堺咲子汐施獅鹿叱屍桟〒塞腰 砦搾鮫塞作菜咲漉鎬問ɔ作臍さ鷺史諮式姿質黻棊イ 鉄噴燒逵嗷桟癆財腰 鑢ŠW崎昨漉緑杢倫H作梏菜咲補鐵噴燒桟 Sybyl6.91 崎貼耆菜漉MD ゝ五昨 MMFF94s 堀寉 採皿侾饋┞柱貼ブ壎埼邇㊌0倫壎桟猜最財単磔 堀寉桟ブ最咲漉㎟熾 1200K漉X返搾獅伺璽施脂紙 字昨 1fs 埼菜漉 100 施脂紙字祭埼作イ鉄噴燒桟指 叱字鹿叱屍菜咲 1ns 搾ゝ五桟〒堺財腰 浴攷嗷瘨杢斟Q磔瘜嫗瘇甪痠返攷臍瘥倫痏 胯叛瘜0倫噴燒瘨艢瞥 CAMDAS 作鮫晒癆皿傘財弩豁搾史諮式姿質黻棊 イ鉄噴燒搾単採皿0倫噴燒桟突策瞥載財殺作漉畚Š W曄崎麻o斎傘財返攷臍咋倫惨剤胯叛 SUPERPOSE 桟ブ最咲臍咋倫惨剤ゝ五桟〒堺財腰 SUPERPOSE 崎昨漉返攷敏搾緑浴攷嗷 (暉勝嫗∭ 桟 び邇磔 (HP∭漉邇㊌0倫棟濁磔 (HD)漉邇㊌0倫略 朿磔 (HA∭漉邇㊌0倫棟濁/略朿磔 (DA∭搾4ⅲ帮作 彖募菜漉催三滝暘搾彖歳斎桟莟堺財M (暉勝嫗Q磔 M) 埼菜咲↘I載三 (Figure 1)腰材菜咲漉緑杢倫H搾
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05 Organic Cation Transporter 1 (hOCT1)
3D-QSAR
㎲
さ SLC22A
Organic Cation Transporter 1 (OCT1)
㈻ ㎲ [1]
OCT1
㈻
㈻
レ
OCT1 レ
よ よ
スゝ
さ さ
Ligand-Based Drug
Design よ
CAMDAS[2] SUPERPOSE[3]
CoMFA[4]
3D-QSAR
S. H. Wright OCT1
Catalyst
Cerius2
Descriptor-Based QSAR よ[5] QSAR
3D-QSAR
MD
よ
OCT1
CAMDAS
よ
CAMDAS
ゝ
み
さ
Sybyl6.91 MD ゝ MMFF94s
┞
1200K
1fs 100
1ns ゝ
CAMDAS
SUPERPOSE ゝ
SUPERPOSE (
(HP (HD)
(HA / (DA 4
(
) (Figure 1)
㌹
ば 3
┞ 3D-QSAR よ
ゝ
3D-QSAR CoMFA よ
MOPAC2002
MNDO-ESP ゝ CoMFA
ゝ
IC50
log(1/IC50) CoMFA
ゝ 2Å ス
+1 sp3
々 ┞ q2
OCT1
(Training Set: 22 Test Set: 8 )
CAMDAS ゝ
12kcal/mol
(Table 1)
Training Set 22 SUPERPOSE
1 3
Catalyst
(Figure 2)
-O
NH3+
O
OH
Hydrophobic
Hydrogen Donor Hydrogen
Donor/Acceptor
Figure 1.
Hydrophobic
Hydrogen Acceptor
Hydrogen Acceptor
Hydrogen Donor
Hydrogen Donor/Acceptor
!!" #$%&'(')µ*+ ,-.)/0#$%&+12345678
!!" #$%&'(')µ*+ ,-.)/0#$%&+12345678
TEA 168 3.78 196
Clonidine 0.71 6.15 48 Thiamine 434 3.36 108
TPeA 1.8 5.74 6963 Dopamine 487.2 3.31 18
Chloropromazine 4.3 5.37 216 Cyclohexylamine 544 3.26 24
Quinidine 5.4 5.27 202 NMN 1035 2.98 6
9:; 6.5 5.19 5593 Histamine 3007 2.52 23
Crystal violet 7.7 5.11 89 Choline 3540 2.45 17
Pindolol 9.7 5.01 10
Procainamide 14.5 4.84 2021 4-NHEPP 16.2 4.79 61
MPP 15.7 4.80 8 4-NEPP 7.1 5.15 24
Amantadine 18.4 4.74 2 4-NBPP 9.3 5.03 58
Ranitidine 21.7 4.66 7548 3-NHEPP 31.1 4.51 74
TPrA 22 4.66 1974 3-NEPP 28.3 4.55 27
Nicotine 53.2 4.27 32 3-NBPP 5.5 5.26 70
<=>? 80.6 4.09 17 NEQ 67.6 4.17 5
Tyramine 107 3.97 18 NBQ 14.3 4.84 21
Table 1.!!" OCT1 #$%&'()*#+,-.!/01
Training Set
Test Set
TPeA: Tetrapentylammonium, TBA: Tetrabutylammonium, TPrA: Tetrapropylammonium, TEA: Tetraethylammonium, MPP: 1-Methyl-4-phenylpyridinium,
NMN: 1-Methylnicotineamide, NHEQ: 1-(2-Hydroxyethyl)quinolinium, NBQ: 1-(Phenyl)methylquinolinium, NEQ: 1-Ethylquinolinium, #-NHEPP: 1-(2-
Hydroxyethyl)-#-phenylpyridinium, #-NEPP: 1-Ethyl-#-phenylpyridinium, #-NBPP: 1-(Phenyl)methyl-#-pyridinium
OCT1
Training Set 22
SUPERPOSE 10
CoMFA よ
(Table 2) q2 1
㈻ CoMFA よ q2
0.3[6]
CoMFA よ q2
0.3
(Table 2 8 9 10) q2
CoMFA よ
Test Set
8 Training Set
SUPERPOSE 8
root-mean-square error
(RMSE) フ
CoMFA よ
S. H. Wright
Cerius2
QSAR (オ 5)
(Table 3)
(RMSE )
10
CoMFA
Figure 3 10
ゝ ┞ Figure 4
q2 3D-QSAR
Table 3
ッ CoMFA
3D-QSAR Cerius2 QSAR
CoMFA QSAR
3D-QSAR
pattern q2 Spress !"# s r2 F ST EL
1 0.595 0.706 3 0.210 0.964 162.049 0.801 0.199
2 0.631 0.674 3 0.207 0.965 166.497 0.832 0.168
3 0.612 0.691 3 0.196 0.969 185.736 0.818 0.182
4 0.607 0.696 3 0.215 0.963 154.134 0.828 0.172
5 0.584 0.716 3 0.188 0.971 202.075 0.795 0.205
6 0.575 0.704 2 0.318 0.914 100.328 0.821 0.179
7 0.515 0.752 2 0.387 0.871 64.367 0.820 0.180
8 0.673 0.634 3 0.192 0.970 195.116 0.810 0.190
9 0.688 0.619 3 0.204 0.966 171.585 0.819 0.181
10 0.663 0.644 3 0.207 0.965 166.481 0.853 0.147
Cross-Validated Conventional Contribution
Table 2. !"#$%&'()*+,-.CoMFA.!/&0
[1] Koepsell H., Schmitt B. M., Gorboulev V., Rev. Physiol.
Biochem. Pharmacol., 150, 36-90 (2003)
[2] Tsujishita H., Hirono S., J. Compt. Aided. Molec. Design.,
11, 305-315 (1997)
[3] Iwase K., Hirono S., J. Compt. Aided. Molec. Design., 13,
499-512 (1999)
[4] Cramer R. D., Patterson D. E., Bunce J. D., J. Am. Chem.
Soc., 110, 5959-5967 (1988)
[5] Bednarczyk D., Ekins S., Wikel J. H., Wright S. H., Mol.
Pharmacol., 63, 489-498 (2003)
[6] Clark M., Cramer R. D. III, Quant. Stract. Act. Relat., 12,
137-145 (1993)
Figure 4. !"#$%"#&!'()*+(,-./01012(,Cerius234,Training Set 2256718,Test Set 8567
Figure 3.!!" OCT1 # CoMFA $%&'()*'+,-./0'+12./3456+Clonidine7
pattern 8 pattern 9 pattern 10 Cerius2
Measure (µM) Predict (µM) Predict (µM) Predict (µM) Predict (µM)
3_NBPP 5.5 5.6 6.6 7.7 11.4
3_NEPP 28.3 28.1 30.9 24.6 9.4
3_NHEPP 31.1 15.2 29.4 23.6 63.5
NBPP 9.3 14.5 8.2 7.4 8.4
NEPP 7.1 7.4 11.5 15.3 13.9
NHEPP 16.2 14.5 15.7 19.1 38.3
NBQ 14.3 16.0 18.9 21.6 11.5
NEQ 67.6 60.7 47.4 69.0 21.3
RMSE ! 6.46 7.58 5.12 22.72
Test Set"#$
Table 3. !"#$%&'()*+(,-.(/0.!"50)
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