Disease Information

General Information of the Disease (ID: DIS00256)
Name
Parkinson disease
ICD
ICD-11: 8A00
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
Drug Resistance Data Categorized by Drug
Approved Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Levedopa
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Leucine rich repeat kinase 2 (LRRK2) [1]
Resistant Disease Parkinson disease [ICD-11: 8A00.0]
Resistant Drug Levedopa
 Drug Info 
Molecule Alteration Missense mutation
p.I2020T
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 3.05  Å
PDB: 8TXZ
Mutant Type Structure Method: Electron microscopy Resolution: 2.70  Å
PDB: 8TZG
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.18
TM score: 0.95893
Amino acid change:
I2020T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
N
R
R
M
M
K
K
L
L
M
M
I
I
1340
|
V
V
G
G
N
N
T
T
G
G
S
S
G
G
K
K
T
T
T
T
1350
|
L
L
L
L
Q
Q
Q
Q
L
L
M
M
K
K
T
T
K
K
K
K
1360
|
S
S
D
D
L
L
G
G
M
M
Q
Q
S
S
A
A
T
T
V
V
1370
|
G
G
I
I
D
D
V
V
K
K
D
D
W
W
P
P
I
I
Q
Q
1380
|
I
I
R
R
D
D
K
K
R
R
K
K
R
R
D
D
L
L
V
V
1390
|
L
L
N
N
V
V
W
W
D
D
F
F
A
A
G
G
R
R
E
E
1400
|
E
E
F
F
Y
Y
S
S
T
T
H
H
P
P
H
H
F
F
M
M
1410
|
T
T
Q
Q
R
R
A
A
L
L
Y
Y
L
L
A
A
V
V
Y
Y
1420
|
D
D
L
L
S
S
K
K
G
G
Q
Q
A
A
E
E
V
V
D
D
1430
|
A
A
M
M
K
K
P
P
W
W
L
L
F
F
N
N
I
I
K
K
1440
|
A
A
R
R
A
A
S
S
S
S
S
S
P
P
V
V
I
I
L
L
1450
|
V
V
G
G
T
T
H
H
L
L
D
D
V
V
S
S
D
D
E
E
1460
|
K
K
Q
Q
R
R
K
K
A
A
C
C
M
M
S
S
K
K
I
I
1470
|
T
T
K
K
E
E
L
L
L
L
N
N
K
K
R
R
G
G
F
F
1480
|
P
P
A
A
I
I
R
R
D
D
Y
Y
H
H
F
F
V
V
N
N
1490
|
A
A
T
T
E
E
E
E
S
S
D
D
A
A
L
L
A
A
K
K
1500
|
L
L
R
R
K
K
T
T
I
I
I
I
N
N
E
E
S
S
L
L
1510
|
N
N
F
F
K
K
I
I
R
R
D
D
Q
Q
L
L
V
V
V
V
1520
|
G
G
Q
Q
L
L
I
I
P
P
D
D
C
C
Y
Y
V
V
E
E
1530
|
L
L
E
E
K
K
I
I
I
I
L
L
S
S
E
E
R
R
K
K
1540
|
N
N
V
V
P
P
I
I
E
E
F
F
P
P
V
V
I
I
D
D
1550
|
R
R
K
K
R
R
L
L
L
L
Q
Q
L
L
V
V
R
R
E
E
1560
|
N
N
Q
Q
L
L
Q
Q
L
L
D
D
E
E
N
N
E
E
L
L
1570
|
P
P
H
H
A
A
V
V
H
H
F
F
L
L
N
N
E
E
S
S
1580
|
G
G
V
V
L
L
L
L
H
H
F
F
Q
Q
D
D
P
P
A
A
1590
|
L
L
Q
Q
L
L
S
S
D
D
L
L
Y
Y
F
F
V
V
E
E
1600
|
P
P
K
K
W
W
L
L
C
C
K
K
I
I
M
M
A
A
Q
Q
1610
|
I
I
L
L
T
T
V
V
K
K
V
V
E
E
G
G
C
C
P
P
1620
|
K
K
H
H
P
P
K
K
G
G
I
I
I
I
S
S
R
R
R
R
1630
|
D
D
V
V
E
E
K
K
F
F
L
L
S
S
K
K
K
K
R
R
1640
|
K
K
F
F
P
P
K
K
N
N
Y
Y
M
M
S
S
Q
Q
Y
Y
1650
|
F
F
K
K
L
L
L
L
E
E
K
K
F
F
Q
Q
I
I
A
A
1660
|
L
L
P
P
I
I
G
G
E
E
E
E
Y
Y
L
L
L
L
V
V
1670
|
P
P
S
S
S
S
L
L
S
S
D
D
H
H
R
R
P
P
V
V
1680
|
I
I
E
E
L
L
P
P
H
H
C
C
E
E
N
N
S
S
E
E
1690
|
I
I
I
I
I
I
R
R
L
L
Y
Y
E
E
M
M
P
P
Y
Y
1700
|
F
F
P
P
M
M
G
G
F
F
W
W
S
S
R
R
L
L
I
I
1710
|
N
N
R
R
L
L
L
L
E
E
I
I
S
S
P
P
Y
Y
M
M
1720
|
L
L
S
S
G
G
R
R
E
E
R
R
A
A
L
L
R
R
P
P
1730
|
N
N
R
R
M
M
Y
Y
W
W
R
R
Q
Q
G
G
I
I
Y
Y
1740
|
L
L
N
N
W
W
S
S
P
P
E
E
A
A
Y
Y
C
C
L
L
1750
|
V
V
G
G
S
S
E
E
V
V
L
L
D
D
N
N
H
H
P
P
1760
|
E
E
S
S
F
F
L
L
K
K
I
I
T
T
V
V
P
P
S
S
1770
|
C
C
R
R
K
K
G
G
C
C
I
I
L
L
L
L
G
G
Q
Q
1780
|
V
V
V
V
D
D
H
H
I
I
D
D
S
S
L
L
M
M
E
E
1790
|
E
E
W
W
F
F
P
P
G
G
L
L
L
L
E
E
I
I
D
D
1800
|
I
I
C
C
G
G
E
E
G
G
E
E
T
T
L
L
L
L
K
K
1810
|
K
K
W
W
A
A
L
L
Y
Y
S
S
F
F
N
N
D
D
G
G
1820
|
E
E
E
E
H
H
Q
Q
K
K
I
I
L
L
L
L
D
D
D
D
1830
|
L
L
M
M
K
K
K
K
A
A
E
E
E
E
G
G
D
D
L
L
1840
|
L
L
V
V
N
N
P
P
D
D
Q
Q
P
P
R
R
L
L
T
T
1850
|
I
I
P
P
I
I
S
S
Q
Q
I
I
A
A
P
P
D
D
L
L
1860
|
I
I
L
L
A
A
D
D
L
L
P
P
R
R
N
N
I
I
M
M
1870
|
L
L
N
N
N
N
D
D
E
E
L
L
E
E
F
F
E
E
Q
Q
1880
|
A
A
P
P
E
E
F
F
L
L
L
L
G
G
D
D
G
G
S
S
1890
|
F
F
G
G
S
S
V
V
Y
Y
R
R
A
A
A
A
Y
Y
E
E
1900
|
G
G
E
E
E
E
V
V
A
A
V
V
K
K
I
I
F
F
N
N
1910
|
K
K
H
H
T
T
S
S
L
L
R
R
L
L
L
L
R
R
Q
Q
1920
|
E
E
L
L
V
V
V
V
L
L
C
C
H
H
L
L
H
H
H
H
1930
|
P
P
S
S
L
L
I
I
S
S
L
L
L
L
A
A
A
A
G
G
1940
|
I
I
R
R
P
P
R
R
M
M
L
L
V
V
M
M
E
E
L
L
1950
|
A
A
S
S
K
K
G
G
S
S
L
L
D
D
R
R
L
L
L
L
1960
|
Q
Q
Q
Q
D
D
K
K
A
A
S
S
L
L
T
T
R
R
T
T
1970
|
L
L
Q
Q
H
H
R
R
I
I
A
A
L
L
H
H
V
V
A
A
1980
|
D
D
G
G
L
L
R
R
Y
Y
L
L
H
H
S
S
A
A
M
M
1990
|
I
I
I
I
Y
Y
R
R
D
D
L
L
K
K
P
P
H
H
N
N
2000
|
V
V
L
L
L
L
F
F
T
T
L
L
Y
Y
P
P
N
N
A
A
2010
|
A
A
I
I
I
I
A
A
K
K
I
I
A
A
D
D
Y
Y
G
G
2020
|
I
T
A
A
Q
Q
Y
Y
C
C
C
C
R
R
M
M
G
G
I
I
2030
|
K
K
T
T
S
S
E
E
G
G
T
T
P
P
G
G
F
F
R
R
2040
|
A
A
P
P
E
E
V
V
A
A
R
R
G
G
N
N
V
V
I
I
2050
|
Y
Y
N
N
Q
Q
Q
Q
A
A
D
D
V
V
Y
Y
S
S
F
F
2060
|
G
G
L
L
L
L
L
L
Y
Y
D
D
I
I
L
L
T
T
T
T
2070
|
G
G
G
G
R
R
I
I
V
V
E
E
G
G
L
L
K
K
F
F
2080
|
P
P
N
N
E
E
F
F
D
D
E
E
L
L
E
E
I
I
Q
Q
2090
|
G
G
K
K
L
L
P
P
D
D
P
P
V
V
K
K
E
E
Y
Y
2100
|
G
G
C
C
A
A
P
P
W
W
P
P
M
M
V
V
E
E
K
K
2110
|
L
L
I
I
K
K
Q
Q
C
C
L
L
K
K
E
E
N
N
P
P
2120
|
Q
Q
E
E
R
R
P
P
T
T
S
S
A
A
Q
Q
V
V
F
F
2130
|
D
D
I
I
L
L
N
N
S
S
A
A
E
E
L
L
V
V
C
C
2140
|
L
L
T
T
R
R
R
R
I
I
L
L
L
L
P
P
K
K
N
N
2150
|
V
V
I
I
V
V
E
E
C
C
M
M
V
V
A
A
T
T
H
H
2160
|
H
H
N
N
S
S
R
R
N
N
A
A
S
S
I
I
W
W
L
L
2170
|
G
G
C
C
G
G
H
H
T
T
D
D
R
R
G
G
Q
Q
L
L
2180
|
S
S
F
F
L
L
D
D
L
L
N
N
T
T
E
E
G
G
Y
Y
2190
|
T
T
S
S
E
E
E
E
V
V
A
A
D
D
S
S
R
R
I
I
2200
|
L
L
C
C
L
L
A
A
L
L
V
V
H
H
L
L
P
P
V
V
2210
|
E
E
K
K
E
E
S
S
W
W
I
I
V
V
S
S
G
G
T
T
2220
|
Q
Q
S
S
G
G
T
T
L
L
L
L
V
V
I
I
N
N
T
T
2230
|
E
E
D
D
G
G
K
K
K
K
R
R
H
H
T
T
L
L
E
E
2240
|
K
K
M
M
T
T
D
D
S
S
V
V
T
T
C
C
L
L
Y
Y
2250
|
C
C
N
N
S
S
F
F
S
S
K
K
Q
Q
S
S
K
K
Q
Q
2260
|
K
K
N
N
F
F
L
L
L
L
V
V
G
G
T
T
A
A
D
D
2270
|
G
G
K
K
L
L
A
A
I
I
F
F
E
E
D
D
K
K
T
T
2280
|
V
V
K
K
L
L
K
K
G
G
A
A
A
A
P
P
L
L
K
K
2290
|
I
I
L
L
N
N
I
I
G
G
N
N
V
V
S
S
T
T
P
P
2300
|
L
L
M
M
C
C
L
L
S
S
E
E
S
S
T
T
N
N
S
S
2310
|
T
T
E
E
R
R
N
N
V
V
M
M
W
W
G
G
G
G
C
C
2320
|
G
G
T
T
K
K
I
I
F
F
S
S
F
F
S
S
N
N
D
D
2330
|
F
F
T
T
I
I
Q
Q
K
K
L
L
I
I
E
E
T
T
R
R
2340
|
T
T
S
S
Q
Q
L
L
F
F
S
S
Y
Y
A
A
A
A
F
F
2350
|
S
S
D
D
S
S
N
N
I
I
I
I
T
T
V
V
V
V
V
V
2360
|
D
D
T
T
A
A
L
L
Y
Y
I
I
A
A
K
K
Q
Q
N
N
2370
|
S
S
P
P
V
V
V
V
E
E
V
V
W
W
D
D
K
K
K
K
2380
|
T
T
E
E
K
K
L
L
C
C
G
G
L
L
I
I
D
D
C
C
2390
|
V
V
H
H
F
F
L
L
R
R
E
E
V
V
M
M
V
V
K
K
2400
|
E
E
N
N
K
K
E
E
S
S
K
K
H
H
K
K
M
M
S
S
2410
|
Y
Y
S
S
G
G
R
R
V
V
K
K
T
T
L
L
C
C
L
L
2420
|
Q
Q
K
K
N
N
T
T
A
A
L
L
W
W
I
I
G
G
T
T
2430
|
G
G
G
G
G
G
H
H
I
I
L
L
L
L
L
L
D
D
L
L
2440
|
S
S
T
T
R
R
R
R
L
L
I
I
R
R
V
V
I
I
Y
Y
2450
|
N
N
F
F
C
C
N
N
S
S
V
V
R
R
V
V
M
M
M
M
2460
|
T
T
A
A
Q
Q
L
L
G
G
S
S
L
L
K
K
N
N
V
V
2470
|
M
M
L
L
V
V
L
L
G
G
Y
Y
N
N
R
R
K
K
N
N
2480
|
T
T
E
E
G
G
T
T
Q
Q
K
K
Q
Q
K
K
E
E
I
I
2490
|
Q
Q
S
S
C
C
L
L
T
T
V
V
W
W
D
D
I
I
N
N
2500
|
L
L
P
P
H
H
E
E
V
V
Q
Q
N
N
L
L
E
E
K
K
2510
|
H
H
I
I
E
E
V
V
R
R
K
K
E
E
L
L
A
A
E
E
2520
|
K
K
M
M
R
R
R
-
T
-
S
-
V
-
E
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Drug Resistance		 Molecular docking analysis; Molecular dynamic simulation assay
Mechanism Description The deleterious mutations G2019S and I2020T in the kinase domain were playing a key role in causing resistance to drug levedopa.
Key Molecule: Leucine rich repeat kinase 2 (LRRK2) [1]
Resistant Disease Parkinson disease [ICD-11: 8A00.0]
Resistant Drug Levedopa
 Drug Info 
Molecule Alteration Missense mutation
p.G2019S
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 3.05  Å
PDB: 8TXZ
Mutant Type Structure Method: Electron microscopy Resolution: 2.70  Å
PDB: 8TZC
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.27
TM score: 0.89948
Amino acid change:
G2019S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
N
R
R
M
M
K
K
L
L
M
M
I
I
1340
|
V
V
G
G
N
N
T
T
G
G
S
S
G
G
K
K
T
T
T
T
1350
|
L
L
L
L
Q
Q
Q
Q
L
L
M
M
K
K
T
T
K
K
K
K
1360
|
S
S
D
D
L
L
G
G
M
M
Q
Q
S
S
A
A
T
T
V
V
1370
|
G
G
I
I
D
D
V
V
K
K
D
D
W
W
P
P
I
I
Q
Q
1380
|
I
I
R
R
D
D
K
K
R
R
K
K
R
R
D
D
L
L
V
V
1390
|
L
L
N
N
V
V
W
W
D
D
F
F
A
A
G
G
R
R
E
E
1400
|
E
E
F
F
Y
Y
S
S
T
T
H
H
P
P
H
H
F
F
M
M
1410
|
T
T
Q
Q
R
R
A
A
L
L
Y
Y
L
L
A
A
V
V
Y
Y
1420
|
D
D
L
L
S
S
K
K
G
G
Q
Q
A
A
E
E
V
V
D
D
1430
|
A
A
M
M
K
K
P
P
W
W
L
L
F
F
N
N
I
I
K
K
1440
|
A
A
R
R
A
A
S
S
S
S
S
S
P
P
V
V
I
I
L
L
1450
|
V
V
G
G
T
T
H
H
L
L
D
D
V
V
S
S
D
D
E
E
1460
|
K
K
Q
Q
R
R
K
K
A
A
C
C
M
M
S
S
K
K
I
I
1470
|
T
T
K
K
E
E
L
L
L
L
N
N
K
K
R
R
G
G
F
F
1480
|
P
P
A
A
I
I
R
R
D
D
Y
Y
H
H
F
F
V
V
N
N
1490
|
A
A
T
T
E
E
E
E
S
S
D
D
A
A
L
L
A
A
K
K
1500
|
L
L
R
R
K
K
T
T
I
I
I
I
N
N
E
E
S
S
L
L
1510
|
N
N
F
F
K
K
I
I
R
R
D
D
Q
Q
L
L
V
V
V
V
1520
|
G
G
Q
Q
L
L
I
I
P
P
D
D
C
C
Y
Y
V
V
E
E
1530
|
L
L
E
E
K
K
I
I
I
I
L
L
S
S
E
E
R
R
K
K
1540
|
N
N
V
V
P
P
I
I
E
E
F
F
P
P
V
V
I
I
D
D
1550
|
R
R
K
K
R
R
L
L
L
L
Q
Q
L
L
V
V
R
R
E
E
1560
|
N
N
Q
Q
L
L
Q
Q
L
L
D
D
E
E
N
N
E
E
L
L
1570
|
P
P
H
H
A
A
V
V
H
H
F
F
L
L
N
N
E
E
S
S
1580
|
G
G
V
V
L
L
L
L
H
H
F
F
Q
Q
D
D
P
P
A
A
1590
|
L
L
Q
Q
L
L
S
S
D
D
L
L
Y
Y
F
F
V
V
E
E
1600
|
P
P
K
K
W
W
L
L
C
C
K
K
I
I
M
M
A
A
Q
Q
1610
|
I
I
L
L
T
T
V
V
K
K
V
V
E
E
G
G
C
C
P
P
1620
|
K
K
H
H
P
P
K
K
G
G
I
I
I
I
S
S
R
R
R
R
1630
|
D
D
V
V
E
E
K
K
F
F
L
L
S
S
K
K
K
K
R
R
1640
|
K
K
F
F
P
P
K
K
N
N
Y
Y
M
M
S
S
Q
Q
Y
Y
1650
|
F
F
K
K
L
L
L
L
E
E
K
K
F
F
Q
Q
I
I
A
A
1660
|
L
L
P
P
I
I
G
G
E
E
E
E
Y
Y
L
L
L
L
V
V
1670
|
P
P
S
S
S
S
L
L
S
S
D
D
H
H
R
R
P
P
V
V
1680
|
I
I
E
E
L
L
P
P
H
H
C
C
E
E
N
N
S
S
E
E
1690
|
I
I
I
I
I
I
R
R
L
L
Y
Y
E
E
M
M
P
P
Y
Y
1700
|
F
F
P
P
M
M
G
G
F
F
W
W
S
S
R
R
L
L
I
I
1710
|
N
N
R
R
L
L
L
L
E
E
I
I
S
S
P
P
Y
Y
M
M
1720
|
L
L
S
S
G
G
R
R
E
E
R
R
A
A
L
L
R
R
P
P
1730
|
N
N
R
R
M
M
Y
Y
W
W
R
R
Q
Q
G
G
I
I
Y
Y
1740
|
L
L
N
N
W
W
S
S
P
P
E
E
A
A
Y
Y
C
C
L
L
1750
|
V
V
G
G
S
S
E
E
V
V
L
L
D
D
N
N
H
H
P
P
1760
|
E
E
S
S
F
F
L
L
K
K
I
I
T
T
V
V
P
P
S
S
1770
|
C
C
R
R
K
K
G
G
C
C
I
I
L
L
L
L
G
G
Q
Q
1780
|
V
V
V
V
D
D
H
H
I
I
D
D
S
S
L
L
M
M
E
E
1790
|
E
E
W
W
F
F
P
P
G
G
L
L
L
L
E
E
I
I
D
D
1800
|
I
I
C
C
G
G
E
E
G
G
E
E
T
T
L
L
L
L
K
K
1810
|
K
K
W
W
A
A
L
L
Y
Y
S
S
F
F
N
N
D
D
G
G
1820
|
E
E
E
E
H
H
Q
Q
K
K
I
I
L
L
L
L
D
D
D
D
1830
|
L
L
M
M
K
K
K
K
A
A
E
E
E
E
G
G
D
D
L
L
1840
|
L
L
V
V
N
N
P
P
D
D
Q
Q
P
P
R
R
L
L
T
T
1850
|
I
I
P
P
I
I
S
S
Q
Q
I
I
A
A
P
P
D
D
L
L
1860
|
I
I
L
L
A
A
D
D
L
L
P
P
R
R
N
N
I
I
M
M
1870
|
L
L
N
N
N
N
D
D
E
E
L
L
E
E
F
F
E
E
Q
Q
1880
|
A
A
P
P
E
E
F
F
L
L
L
L
G
G
D
D
G
G
S
S
1890
|
F
F
G
G
S
S
V
V
Y
Y
R
R
A
A
A
A
Y
Y
E
E
1900
|
G
G
E
E
E
E
V
V
A
A
V
V
K
K
I
I
F
F
N
N
1910
|
K
K
H
H
T
T
S
S
L
L
R
R
L
L
L
L
R
R
Q
Q
1920
|
E
E
L
L
V
V
V
V
L
L
C
C
H
H
L
L
H
H
H
H
1930
|
P
P
S
S
L
L
I
I
S
S
L
L
L
L
A
A
A
A
G
G
1940
|
I
I
R
R
P
P
R
R
M
M
L
L
V
V
M
M
E
E
L
L
1950
|
A
A
S
S
K
K
G
G
S
S
L
L
D
D
R
R
L
L
L
L
1960
|
Q
Q
Q
Q
D
D
K
K
A
A
S
S
L
L
T
T
R
R
T
T
1970
|
L
L
Q
Q
H
H
R
R
I
I
A
A
L
L
H
H
V
V
A
A
1980
|
D
D
G
G
L
L
R
R
Y
Y
L
L
H
H
S
S
A
A
M
M
1990
|
I
I
I
I
Y
Y
R
R
D
D
L
L
K
K
P
P
H
H
N
N
2000
|
V
V
L
L
L
L
F
F
T
T
L
L
Y
Y
P
P
N
N
A
A
2010
|
A
A
I
I
I
I
A
A
K
K
I
I
A
A
D
D
Y
Y
G
S
2020
|
I
I
A
A
Q
Q
Y
Y
C
C
C
C
R
R
M
M
G
G
I
I
2030
|
K
K
T
T
S
S
E
E
G
G
T
T
P
P
G
G
F
F
R
R
2040
|
A
A
P
P
E
E
V
V
A
A
R
R
G
G
N
N
V
V
I
I
2050
|
Y
Y
N
N
Q
Q
Q
Q
A
A
D
D
V
V
Y
Y
S
S
F
F
2060
|
G
G
L
L
L
L
L
L
Y
Y
D
D
I
I
L
L
T
T
T
T
2070
|
G
G
G
G
R
R
I
I
V
V
E
E
G
G
L
L
K
K
F
F
2080
|
P
P
N
N
E
E
F
F
D
D
E
E
L
L
E
E
I
I
Q
Q
2090
|
G
G
K
K
L
L
P
P
D
D
P
P
V
V
K
K
E
E
Y
Y
2100
|
G
G
C
C
A
A
P
P
W
W
P
P
M
M
V
V
E
E
K
K
2110
|
L
L
I
I
K
K
Q
Q
C
C
L
L
K
K
E
E
N
N
P
P
2120
|
Q
Q
E
E
R
R
P
P
T
T
S
S
A
A
Q
Q
V
V
F
F
2130
|
D
D
I
I
L
L
N
N
S
S
A
A
E
E
L
L
V
V
C
C
2140
|
L
L
T
T
R
R
R
R
I
I
L
L
L
L
P
P
K
K
N
N
2150
|
V
V
I
I
V
V
E
E
C
C
M
M
V
V
A
A
T
T
H
H
2160
|
H
H
N
N
S
S
R
R
N
N
A
A
S
S
I
I
W
W
L
L
2170
|
G
G
C
C
G
G
H
H
T
T
D
D
R
R
G
G
Q
Q
L
L
2180
|
S
S
F
F
L
L
D
D
L
L
N
N
T
T
E
E
G
G
Y
Y
2190
|
T
T
S
S
E
E
E
E
V
V
A
A
D
D
S
S
R
R
I
I
2200
|
L
L
C
C
L
L
A
A
L
L
V
V
H
H
L
L
P
P
V
V
2210
|
E
E
K
K
E
E
S
S
W
W
I
I
V
V
S
S
G
G
T
T
2220
|
Q
Q
S
S
G
G
T
T
L
L
L
L
V
V
I
I
N
N
T
T
2230
|
E
E
D
D
G
G
K
K
K
K
R
R
H
H
T
T
L
L
E
E
2240
|
K
K
M
M
T
T
D
D
S
S
V
V
T
T
C
C
L
L
Y
Y
2250
|
C
C
N
N
S
S
F
F
S
S
K
K
Q
Q
S
S
K
K
Q
Q
2260
|
K
K
N
N
F
F
L
L
L
L
V
V
G
G
T
T
A
A
D
D
2270
|
G
G
K
K
L
L
A
A
I
I
F
F
E
E
D
D
K
K
T
T
2280
|
V
V
K
K
L
L
K
K
G
G
A
A
A
A
P
P
L
L
K
K
2290
|
I
I
L
L
N
N
I
I
G
G
N
N
V
V
S
S
T
T
P
P
2300
|
L
L
M
M
C
C
L
L
S
S
E
E
S
S
T
T
N
N
S
S
2310
|
T
T
E
E
R
R
N
N
V
V
M
M
W
W
G
G
G
G
C
C
2320
|
G
G
T
T
K
K
I
I
F
F
S
S
F
F
S
S
N
N
D
D
2330
|
F
F
T
T
I
I
Q
Q
K
K
L
L
I
I
E
E
T
T
R
R
2340
|
T
T
S
S
Q
Q
L
L
F
F
S
S
Y
Y
A
A
A
A
F
F
2350
|
S
S
D
D
S
S
N
N
I
I
I
I
T
T
V
V
V
V
V
V
2360
|
D
D
T
T
A
A
L
L
Y
Y
I
I
A
A
K
K
Q
Q
N
N
2370
|
S
S
P
P
V
V
V
V
E
E
V
V
W
W
D
D
K
K
K
K
2380
|
T
T
E
E
K
K
L
L
C
C
G
G
L
L
I
I
D
D
C
C
2390
|
V
V
H
H
F
F
L
L
R
R
E
E
V
V
M
M
V
V
K
K
2400
|
E
E
N
N
K
K
E
E
S
S
K
K
H
H
K
K
M
M
S
S
2410
|
Y
Y
S
S
G
G
R
R
V
V
K
K
T
T
L
L
C
C
L
L
2420
|
Q
Q
K
K
N
N
T
T
A
A
L
L
W
W
I
I
G
G
T
T
2430
|
G
G
G
G
G
G
H
H
I
I
L
L
L
L
L
L
D
D
L
L
2440
|
S
S
T
T
R
R
R
R
L
L
I
I
R
R
V
V
I
I
Y
Y
2450
|
N
N
F
F
C
C
N
N
S
S
V
V
R
R
V
V
M
M
M
M
2460
|
T
T
A
A
Q
Q
L
L
G
G
S
S
L
L
K
K
N
N
V
V
2470
|
M
M
L
L
V
V
L
L
G
G
Y
Y
N
N
R
R
K
K
N
N
2480
|
T
T
E
E
G
G
T
T
Q
Q
K
K
Q
Q
K
K
E
E
I
I
2490
|
Q
Q
S
S
C
C
L
L
T
T
V
V
W
W
D
D
I
I
N
N
2500
|
L
L
P
P
H
H
E
E
V
V
Q
Q
N
N
L
L
E
E
K
K
2510
|
H
H
I
I
E
E
V
V
R
R
K
K
E
E
L
L
A
A
E
E
2520
|
K
K
M
M
R
R
R
R
T
T
S
S
V
V
E
E
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Drug Resistance		 Molecular docking analysis; Molecular dynamic simulation assay
Mechanism Description The deleterious mutations G2019S and I2020T in the kinase domain were playing a key role in causing resistance to drug levedopa.
Rotenone
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Small nucleolar RNA host gene 14 (SNHG14) [2]
Resistant Disease Parkinson disease [ICD-11: 8A00.0]
Resistant Drug Rotenone
 Drug Info 
Molecule Alteration Up-regulation
Interaction
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation SNHG14/miR-133b/alpha -syn signaling pathway Inhibition hsa04933
In Vitro Model MN9D cells N.A. Mus musculus (Mouse) CVCL_M067
In Vivo Model C57BL/6 mice xenograft model Mus musculus
Experiment for
Molecule Alteration		 Knockdown assay
Experiment for
Drug Resistance		 Motor function assessment assay; CCK8 assay; ROS staining and detection assay
Mechanism Description Silence of SNHG14 mitigates dopaminergic neuron injury by down-regulating alpha-syn via targeting miR-133b, which contributes to improving PD.
Investigative Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Cyperquat
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Non-coding RNA activated by DNA damage (NORAD) [3]
Resistant Disease Parkinson disease [ICD-11: 8A00.0]
Resistant Drug Cyperquat
 Drug Info 
Molecule Alteration Down-regulation
Expression
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SH-SY5Y cells Abdomen Homo sapiens (Human) CVCL_0019
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 XTT assay; TUNEL assay; caspase 3/7 activity fluorescence measurement; Total Reactive Oxygen Species assay; Pierce LDH Cytotoxicity assay
Mechanism Description NORAD downregulation was found to significantly deteriorate MPP+-induced cytotoxicity in SH-SY5Y cells.
Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [4]
Resistant Disease Parkinson disease [ICD-11: 8A00.0]
Resistant Drug Cyperquat
 Drug Info 
Molecule Alteration Up-regulation
Interaction
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SH-SY6Y cells N.A. N.A. N.A.
Experiment for
Molecule Alteration		 Mimic assay; qRT-PCR; RNA pull down assay; RIP experiments assay; ELISA assay; Knockdown assay
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description NEAT1 may regulate MPP+ induced neuronal injury by targeting miR-124 in SH-SY5Y cells.
References
Ref 1 Exploring the functional impact of mutational drift in LRRK2 gene and identification of specific inhibitors for the treatment of Parkinson disease .J Cell Biochem. 2018 Jun;119(6):4878-4889. doi: 10.1002/jcb.26703. Epub 2018 Mar 9. 10.1002/jcb.26703
Ref 2 Dopaminergic neuron injury in Parkinson's disease is mitigated by interfering lncRNA SNHG14 expression to regulate the miR-133b/ Alpha-synuclein pathwayAging (Albany NY). 2019 Nov 4;11(21):9264-9279. doi: 10.18632/aging.102330. Epub 2019 Nov 4.
Ref 3 Long noncoding RNA NORAD regulates MPP+-induced Parkinson's disease model cellsJ Chem Neuroanat. 2019 Nov;101:101668. doi: 10.1016/j.jchemneu.2019.101668. Epub 2019 Aug 14.
Ref 4 NEAT1 regulates MPP(+)-induced neuronal injury by targeting miR-124 in neuroblastoma cellsNeurosci Lett. 2019 Aug 24;708:134340. doi: 10.1016/j.neulet.2019.134340. Epub 2019 Jun 19.

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