Post on 26-Jun-2020
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
nakait@pharm.kitasato-u.ac.jp
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)