药学学报

NO.	Name	Chemical formula
1	Isorhamnetin	C₁₆H₁₂O₇
2	Quercetin	C₁₅H₁₀O₇
3	Kaempferol	C₁₅H₁₀O₆
4	Saikosaponin D	C₄₂H₆₈O₁₃
5	Saikosaponin B1	C₄₂H₆₈O₁₃
6	Saikosaponin B2	C₄₂H₆₈O₁₃
7	Saikosaponin A	C₄₂H₆₈O₁₃
8	D1	C₁₅H₁₈O
9	D2	C₁₅H₁₈O
10	D3	C₁₇H₂₂O
11	D4	C₁₇H₂₂O
12	D5	C₁₅H₁₈O
13	D6	C₁₇H₂₀O₂
14	D7	C₁₇H₂₀O₂
15	D8	C₁₇H₂₂O

NO.

Name

Chemical formula

Isorhamnetin

C₁₆H₁₂O₇

Quercetin

C₁₅H₁₀O₇

Kaempferol

C₁₅H₁₀O₆

Saikosaponin D

C₄₂H₆₈O₁₃

Saikosaponin B1

C₄₂H₆₈O₁₃

Saikosaponin B2

C₄₂H₆₈O₁₃

Saikosaponin A

C₄₂H₆₈O₁₃

C₁₅H₁₈O

C₁₇H₂₂O

C₁₅H₁₈O

C₁₇H₂₀O₂

C₁₇H₂₂O

NO.	Name	Chemical formula
1	Isorhamnetin	C₁₆H₁₂O₇
2	Quercetin	C₁₅H₁₀O₇
3	Kaempferol	C₁₅H₁₀O₆
4	Saikosaponin D	C₄₂H₆₈O₁₃
5	Saikosaponin B1	C₄₂H₆₈O₁₃
6	Saikosaponin B2	C₄₂H₆₈O₁₃
7	Saikosaponin A	C₄₂H₆₈O₁₃
8	D1	C₁₅H₁₈O
9	D2	C₁₅H₁₈O
10	D3	C₁₇H₂₂O
11	D4	C₁₇H₂₂O
12	D5	C₁₅H₁₈O
13	D6	C₁₇H₂₀O₂
14	D7	C₁₇H₂₀O₂
15	D8	C₁₇H₂₂O

NO.

Name

Chemical formula

Isorhamnetin

C₁₆H₁₂O₇

Quercetin

C₁₅H₁₀O₇

Kaempferol

C₁₅H₁₀O₆

Saikosaponin D

C₄₂H₆₈O₁₃

Saikosaponin B1

C₄₂H₆₈O₁₃

Saikosaponin B2

C₄₂H₆₈O₁₃

Saikosaponin A

C₄₂H₆₈O₁₃

C₁₅H₁₈O

C₁₇H₂₂O

C₁₅H₁₈O

C₁₇H₂₀O₂

C₁₇H₂₂O

NO.	PDB ID	Target
1	1A8M	TNF
2	3BWY	COMT
3	1P93	NR3C1
4	2Z5X	MAOA
5	1MLW	TPH1
6	3CQW	AKT1
7	1WWB	NTRK2
8	1J1B	GSK3B
9	2A3I	NR3C2
10	1V04	PON1
11	2CYK	IL4
12	1GFW	CASP3
13	2HHA	DPP4
14	1ZEO	PPARG
15	1HSZ	ADH1B
16	1GOS	MAOB
17	1DIA	MTHFD1
18	1R5K	ESR1
19	1E3G	AR
20	1DB1	VDR
21	2C9V	SOD1
22	1QKM	ESR2
23	1S8C	HMOX1
24	2OJ9	IGF1R
25	1A9U	MAPK14
26	1FT4	TNFRSF1A
27	1OPL	ABL1
28	1OF7	ALDH2
29	1TVO	MAPK1
30	2FGI	FGFR1
31	1XU9	HSD11B1
32	1HT0	ADH1C
33	1GMN	HGF
34	1Z6T	APAF1
35	1J8F	SIRT2
36	1J99	SULT2A1
37	2PVY	FGFR2
38	1UWJ	BRAF
39	5P21	HRAS
40	2BX8	ALB
41	1TYL	INS
42	1IMB	IMPA1
43	1ZBQ	HSD17B4
44	1W22	HDAC8
45	2CZH	IMPA2
46	2AUH	INSR
47	1B1C	POR
48	1CYN	PPIB
49	1A3B	F2
50	1QAB	RBP4

NO.

PDB ID

Target

1A8M

TNF

3BWY

COMT

1P93

NR3C1

2Z5X

MAOA

1MLW

TPH1

3CQW

AKT1

1WWB

NTRK2

1J1B

GSK3B

2A3I

NR3C2

1V04

PON1

2CYK

IL4

1GFW

CASP3

2HHA

DPP4

1ZEO

PPARG

1HSZ

ADH1B

1GOS

MAOB

1DIA

MTHFD1

1R5K

ESR1

1E3G

1DB1

VDR

2C9V

SOD1

1QKM

ESR2

1S8C

HMOX1

2OJ9

IGF1R

1A9U

MAPK14

1FT4

TNFRSF1A

1OPL

ABL1

1OF7

ALDH2

1TVO

MAPK1

2FGI

FGFR1

1XU9

HSD11B1

1HT0

ADH1C

1GMN

HGF

1Z6T

APAF1

1J8F

SIRT2

1J99

SULT2A1

2PVY

FGFR2

1UWJ

BRAF

5P21

HRAS

2BX8

ALB

1TYL

INS

1IMB

IMPA1

1ZBQ

HSD17B4

1W22

HDAC8

2CZH

IMPA2

2AUH

INSR

1B1C

POR

1CYN

PPIB

1A3B

1QAB

RBP4

NO.	PDB ID	Target
1	1A8M	TNF
2	3BWY	COMT
3	1P93	NR3C1
4	2Z5X	MAOA
5	1MLW	TPH1
6	3CQW	AKT1
7	1WWB	NTRK2
8	1J1B	GSK3B
9	2A3I	NR3C2
10	1V04	PON1
11	2CYK	IL4
12	1GFW	CASP3
13	2HHA	DPP4
14	1ZEO	PPARG
15	1HSZ	ADH1B
16	1GOS	MAOB
17	1DIA	MTHFD1
18	1R5K	ESR1
19	1E3G	AR
20	1DB1	VDR
21	2C9V	SOD1
22	1QKM	ESR2
23	1S8C	HMOX1
24	2OJ9	IGF1R
25	1A9U	MAPK14
26	1FT4	TNFRSF1A
27	1OPL	ABL1
28	1OF7	ALDH2
29	1TVO	MAPK1
30	2FGI	FGFR1
31	1XU9	HSD11B1
32	1HT0	ADH1C
33	1GMN	HGF
34	1Z6T	APAF1
35	1J8F	SIRT2
36	1J99	SULT2A1
37	2PVY	FGFR2
38	1UWJ	BRAF
39	5P21	HRAS
40	2BX8	ALB
41	1TYL	INS
42	1IMB	IMPA1
43	1ZBQ	HSD17B4
44	1W22	HDAC8
45	2CZH	IMPA2
46	2AUH	INSR
47	1B1C	POR
48	1CYN	PPIB
49	1A3B	F2
50	1QAB	RBP4

NO.

PDB ID

Target

1A8M

TNF

3BWY

COMT

1P93

NR3C1

2Z5X

MAOA

1MLW

TPH1

3CQW

AKT1

1WWB

NTRK2

1J1B

GSK3B

2A3I

NR3C2

1V04

PON1

2CYK

IL4

1GFW

CASP3

2HHA

DPP4

1ZEO

PPARG

1HSZ

ADH1B

1GOS

MAOB

1DIA

MTHFD1

1R5K

ESR1

1E3G

1DB1

VDR

2C9V

SOD1

1QKM

ESR2

1S8C

HMOX1

2OJ9

IGF1R

1A9U

MAPK14

1FT4

TNFRSF1A

1OPL

ABL1

1OF7

ALDH2

1TVO

MAPK1

2FGI

FGFR1

1XU9

HSD11B1

1HT0

ADH1C

1GMN

HGF

1Z6T

APAF1

1J8F

SIRT2

1J99

SULT2A1

2PVY

FGFR2

1UWJ

BRAF

5P21

HRAS

2BX8

ALB

1TYL

INS

1IMB

IMPA1

1ZBQ

HSD17B4

1W22

HDAC8

2CZH

IMPA2

2AUH

INSR

1B1C

POR

1CYN

PPIB

1A3B

1QAB

RBP4

NO.	Degree	PDB ID	Target name
1	34	2BX8	ALB
2	32	1TYL	INS
3	25	1A8M	TNF
4	25	3CQW	AKT1
5	25	1TVO	MAPK1

NO.

Degree

PDB ID

Target name

2BX8

ALB

1TYL

INS

1A8M

TNF

3CQW

AKT1

1TVO

MAPK1

NO.	Degree	PDB ID	Target name
1	34	2BX8	ALB
2	32	1TYL	INS
3	25	1A8M	TNF
4	25	3CQW	AKT1
5	25	1TVO	MAPK1

NO.

Degree

PDB ID

Target name

2BX8

ALB

1TYL

INS

1A8M

TNF

3CQW

AKT1

1TVO

MAPK1

Target name	PDB ID	Ingredient	Docking score
AKT1	3CQW	Isorhamnetin	3.679
ALB	2BX8	Isorhamnetin	3.112
INS	1TYL	Isorhamnetin	2.944
MAPK1	1TVO	Isorhamnetin	2.465
TNF	1A8M	Isorhamnetin	3.099
AKT1	3CQW	Kaempferol	6.604
ALB	2BX8	Kaempferol	5.064
INS	1TYL	Kaempferol	5.248
MAPK1	1TVO	Kaempferol	7.877
TNF	1A8M	Kaempferol	6.709
AKT1	3CQW	Quercetin	6.636
ALB	2BX8	Quercetin	4.812
INS	1TYL	Quercetin	5.106
MAPK1	1TVO	Quercetin	7.888
TNF	1A8M	Quercetin	6.574
ALB	2BX8	Saikosaponin D	6.804
TNF	1A8M	Saikosaponin D	5.054
AKT1	3CQW	Saikosaponin B2	5.907
ALB	2BX8	Saikosaponin B2	6.823
ALB	2BX8	Saikosaponin B1	6.828
AKT1	3CQW	D8	5.16
ALB	2BX8	D8	4.833
INS	1TYL	D8	4.674
MAPK1	1TVO	D8	4.716
TNF	1A8M	D8	5.172
AKT1	3CQW	D7	5.034
ALB	2BX8	D7	4.856
INS	1TYL	D7	4.415
MAPK1	1TVO	D7	4.224
TNF	1A8M	D7	4.706
AKT1	3CQW	D6	5.042
ALB	2BX8	D6	4.731
INS	1TYL	D6	4.411
MAPK1	1TVO	D6	4.344
TNF	1A8M	D6	4.732
AKT1	3CQW	D5	4.492
ALB	2BX8	D5	4.402
INS	1TYL	D5	4.081
MAPK1	1TVO	D5	4.083
TNF	1A8M	D5	4.312
AKT1	3CQW	D4	5.159
ALB	2BX8	D4	4.96
INS	1TYL	D4	4.633
MAPK1	1TVO	D4	4.714
TNF	1A8M	D4	4.964
AKT1	3CQW	D3	4.954
ALB	2BX8	D3	4.75
INS	1TYL	D3	4.635
MAPK1	1TVO	D3	4.712
TNF	1A8M	D3	5.154
AKT1	3CQW	D2	4.55
ALB	2BX8	D2	4.343
INS	1TYL	D2	4.078
MAPK1	1TVO	D2	4.082
TNF	1A8M	D2	4.264
AKT1	3CQW	D1	4.319
ALB	2BX8	D1	4.531
INS	1TYL	D1	4.044
MAPK1	1TVO	D1	4.084
TNF	1A8M	D1	4.491

Target name

PDB ID

Ingredient

Docking score

AKT1

3CQW

Isorhamnetin

3.679

ALB

2BX8

Isorhamnetin

3.112

INS

1TYL

Isorhamnetin

2.944

MAPK1

1TVO

Isorhamnetin

2.465

TNF

1A8M

Isorhamnetin

3.099

AKT1

3CQW

Kaempferol

6.604

ALB

2BX8

Kaempferol

5.064

INS

1TYL

Kaempferol

5.248

MAPK1

1TVO

Kaempferol

7.877

TNF

1A8M

Kaempferol

6.709

AKT1

3CQW

Quercetin

6.636

ALB

2BX8

Quercetin

4.812

INS

1TYL

Quercetin

5.106

MAPK1

1TVO

Quercetin

7.888

TNF

1A8M

Quercetin

6.574

ALB

2BX8

Saikosaponin D

6.804

TNF

1A8M

Saikosaponin D

5.054

AKT1

3CQW

Saikosaponin B2

5.907

ALB

2BX8

Saikosaponin B2

6.823

ALB

2BX8

Saikosaponin B1

6.828

AKT1

3CQW

5.16

ALB

2BX8

4.833

INS

1TYL

4.674

MAPK1

1TVO

4.716

TNF

1A8M

5.172

AKT1

3CQW

5.034

ALB

2BX8

4.856

INS

1TYL

4.415

MAPK1

1TVO

4.224

TNF

1A8M

4.706

AKT1

3CQW

5.042

ALB

2BX8

4.731

INS

1TYL

4.411

MAPK1

1TVO

4.344

TNF

1A8M

4.732

AKT1

3CQW

4.492

ALB

2BX8

4.402

INS

1TYL

4.081

MAPK1

1TVO

4.083

TNF

1A8M

4.312

AKT1

3CQW

5.159

ALB

2BX8

4.96

INS

1TYL

4.633

MAPK1

1TVO

4.714

TNF

1A8M

4.964

AKT1

3CQW

4.954

ALB

2BX8

4.75

INS

1TYL

4.635

MAPK1

1TVO

4.712

TNF

1A8M

5.154

AKT1

3CQW

4.55

ALB

2BX8

4.343

INS

1TYL

4.078

MAPK1

1TVO

4.082

TNF

1A8M

4.264

AKT1

3CQW

4.319

ALB

2BX8

4.531

INS

1TYL

4.044

MAPK1

1TVO

4.084

TNF

1A8M

4.491

Target name	PDB ID	Ingredient	Docking score
AKT1	3CQW	Isorhamnetin	3.679
ALB	2BX8	Isorhamnetin	3.112
INS	1TYL	Isorhamnetin	2.944
MAPK1	1TVO	Isorhamnetin	2.465
TNF	1A8M	Isorhamnetin	3.099
AKT1	3CQW	Kaempferol	6.604
ALB	2BX8	Kaempferol	5.064
INS	1TYL	Kaempferol	5.248
MAPK1	1TVO	Kaempferol	7.877
TNF	1A8M	Kaempferol	6.709
AKT1	3CQW	Quercetin	6.636
ALB	2BX8	Quercetin	4.812
INS	1TYL	Quercetin	5.106
MAPK1	1TVO	Quercetin	7.888
TNF	1A8M	Quercetin	6.574
ALB	2BX8	Saikosaponin D	6.804
TNF	1A8M	Saikosaponin D	5.054
AKT1	3CQW	Saikosaponin B2	5.907
ALB	2BX8	Saikosaponin B2	6.823
ALB	2BX8	Saikosaponin B1	6.828
AKT1	3CQW	D8	5.16
ALB	2BX8	D8	4.833
INS	1TYL	D8	4.674
MAPK1	1TVO	D8	4.716
TNF	1A8M	D8	5.172
AKT1	3CQW	D7	5.034
ALB	2BX8	D7	4.856
INS	1TYL	D7	4.415
MAPK1	1TVO	D7	4.224
TNF	1A8M	D7	4.706
AKT1	3CQW	D6	5.042
ALB	2BX8	D6	4.731
INS	1TYL	D6	4.411
MAPK1	1TVO	D6	4.344
TNF	1A8M	D6	4.732
AKT1	3CQW	D5	4.492
ALB	2BX8	D5	4.402
INS	1TYL	D5	4.081
MAPK1	1TVO	D5	4.083
TNF	1A8M	D5	4.312
AKT1	3CQW	D4	5.159
ALB	2BX8	D4	4.96
INS	1TYL	D4	4.633
MAPK1	1TVO	D4	4.714
TNF	1A8M	D4	4.964
AKT1	3CQW	D3	4.954
ALB	2BX8	D3	4.75
INS	1TYL	D3	4.635
MAPK1	1TVO	D3	4.712
TNF	1A8M	D3	5.154
AKT1	3CQW	D2	4.55
ALB	2BX8	D2	4.343
INS	1TYL	D2	4.078
MAPK1	1TVO	D2	4.082
TNF	1A8M	D2	4.264
AKT1	3CQW	D1	4.319
ALB	2BX8	D1	4.531
INS	1TYL	D1	4.044
MAPK1	1TVO	D1	4.084
TNF	1A8M	D1	4.491

Target name

PDB ID

Ingredient

Docking score

AKT1

3CQW

Isorhamnetin

3.679

ALB

2BX8

Isorhamnetin

3.112

INS

1TYL

Isorhamnetin

2.944

MAPK1

1TVO

Isorhamnetin

2.465

TNF

1A8M

Isorhamnetin

3.099

AKT1

3CQW

Kaempferol

6.604

ALB

2BX8

Kaempferol

5.064

INS

1TYL

Kaempferol

5.248

MAPK1

1TVO

Kaempferol

7.877

TNF

1A8M

Kaempferol

6.709

AKT1

3CQW

Quercetin

6.636

ALB

2BX8

Quercetin

4.812

INS

1TYL

Quercetin

5.106

MAPK1

1TVO

Quercetin

7.888

TNF

1A8M

Quercetin

6.574

ALB

2BX8

Saikosaponin D

6.804

TNF

1A8M

Saikosaponin D

5.054

AKT1

3CQW

Saikosaponin B2

5.907

ALB

2BX8

Saikosaponin B2

6.823

ALB

2BX8

Saikosaponin B1

6.828

AKT1

3CQW

5.16

ALB

2BX8

4.833

INS

1TYL

4.674

MAPK1

1TVO

4.716

TNF

1A8M

5.172

AKT1

3CQW

5.034

ALB

2BX8

4.856

INS

1TYL

4.415

MAPK1

1TVO

4.224

TNF

1A8M

4.706

AKT1

3CQW

5.042

ALB

2BX8

4.731

INS

1TYL

4.411

MAPK1

1TVO

4.344

TNF

1A8M

4.732

AKT1

3CQW

4.492

ALB

2BX8

4.402

INS

1TYL

4.081

MAPK1

1TVO

4.083

TNF

1A8M

4.312

AKT1

3CQW

5.159

ALB

2BX8

4.96

INS

1TYL

4.633

MAPK1

1TVO

4.714

TNF

1A8M

4.964

AKT1

3CQW

4.954

ALB

2BX8

4.75

INS

1TYL

4.635

MAPK1

1TVO

4.712

TNF

1A8M

5.154

AKT1

3CQW

4.55

ALB

2BX8

4.343

INS

1TYL

4.078

MAPK1

1TVO

4.082

TNF

1A8M

4.264

AKT1

3CQW

4.319

ALB

2BX8

4.531

INS

1TYL

4.044

MAPK1

1TVO

4.084

TNF

1A8M

4.491

Gene name	Protein class
TNF	Signaling molecule
COMT	Transferase
NR3C1	Transcription factor; receptor; nucleic acid binding
MAOA	Transferase; oxidoreductase; nucleic acid binding
TPH1	Null
AKT1	Transfer/carrier protein; transferase; calcium-binding protein; kinase
NTRK2	Null
GSK3B	Transferase; kinase
NR3C2	Transcription factor; receptor; nucleic acid binding
PON1	Null
IL4	Signaling molecule
CASP3	Protease; enzyme modulator; hydrolase
DPP4	Protease; enzyme modulator; hydrolase
PPARG	Transcription factor; receptor; nucleic acid binding
ADH1B	Oxidoreductase
MAOB	Transferase; oxidoreductase; nucleic acid binding
MTHFD1	Ligase
ESR1	Transcription factor; receptor; nucleic acid binding
AR	Transcription factor; receptor; nucleic acid binding
VDR	Transcription factor; receptor; nucleic acid binding
SOD1	Oxidoreductase
ESR2	Transcription factor; receptor; nucleic acid binding
HMOX1	Oxidoreductase
IGF1R	Null
MAPK14	Transferase; kinase
TNFRSF1A	Receptor
ABL1	Transferase; kinase
ALDH2	Oxidoreductase
MAPK1	Transferase; kinase
FGFR1	Null
HSD11B1	Oxidoreductase
ADH1C	Oxidoreductase
HGF	Protease; enzyme modulator; hydrolase; signaling molecule; calcium-binding protein; receptor
APAF1	Null
SIRT2	Nucleic acid binding; hydrolase
SULT2A1	Transferase
FGFR2	Null
BRAF	Transferase; kinase
HRAS	Enzyme modulator
ALB	Transfer/carrier protein
INS	Null
IMPA1	Phosphatase; hydrolase
HSD17B4	Null
HDAC8	Oxidoreductase; hydrolase; nucleic acid binding
IMPA2	Phosphatase; hydrolase
INSR	Null
POR	Null
PPIB	Isomerase
F2	Protease; hydrolase
RBP4	Transfer/carrier protein

Gene name

Protein class

TNF

Signaling molecule

COMT

Transferase

NR3C1

Transcription factor; receptor; nucleic acid binding

MAOA

Transferase; oxidoreductase; nucleic acid binding

TPH1

Null

AKT1

Transfer/carrier protein; transferase; calcium-binding protein; kinase

NTRK2

Null

GSK3B

Transferase; kinase

NR3C2

Transcription factor; receptor; nucleic acid binding

PON1

Null

IL4

Signaling molecule

CASP3

Protease; enzyme modulator; hydrolase

DPP4

Protease; enzyme modulator; hydrolase

PPARG

Transcription factor; receptor; nucleic acid binding

ADH1B

Oxidoreductase

MAOB

Transferase; oxidoreductase; nucleic acid binding

MTHFD1

Ligase

ESR1

Transcription factor; receptor; nucleic acid binding

VDR

Transcription factor; receptor; nucleic acid binding

SOD1

Oxidoreductase

ESR2

Transcription factor; receptor; nucleic acid binding

HMOX1

Oxidoreductase

IGF1R

Null

MAPK14

Transferase; kinase

TNFRSF1A

Receptor

ABL1

Transferase; kinase

ALDH2

Oxidoreductase

MAPK1

Transferase; kinase

FGFR1

Null

HSD11B1

Oxidoreductase

ADH1C

Oxidoreductase

HGF

Protease; enzyme modulator; hydrolase; signaling molecule; calcium-binding protein; receptor

APAF1

Null

SIRT2

Nucleic acid binding; hydrolase

SULT2A1

Transferase

FGFR2

Null

BRAF

Transferase; kinase

HRAS

Enzyme modulator

ALB

Transfer/carrier protein

INS

Null

IMPA1

Phosphatase; hydrolase

HSD17B4

Null

HDAC8

Oxidoreductase; hydrolase; nucleic acid binding

IMPA2

Phosphatase; hydrolase

INSR

Null

POR

Null

PPIB

Isomerase

Protease; hydrolase

RBP4

Transfer/carrier protein

Gene name	Protein class
TNF	Signaling molecule
COMT	Transferase
NR3C1	Transcription factor; receptor; nucleic acid binding
MAOA	Transferase; oxidoreductase; nucleic acid binding
TPH1	Null
AKT1	Transfer/carrier protein; transferase; calcium-binding protein; kinase
NTRK2	Null
GSK3B	Transferase; kinase
NR3C2	Transcription factor; receptor; nucleic acid binding
PON1	Null
IL4	Signaling molecule
CASP3	Protease; enzyme modulator; hydrolase
DPP4	Protease; enzyme modulator; hydrolase
PPARG	Transcription factor; receptor; nucleic acid binding
ADH1B	Oxidoreductase
MAOB	Transferase; oxidoreductase; nucleic acid binding
MTHFD1	Ligase
ESR1	Transcription factor; receptor; nucleic acid binding
AR	Transcription factor; receptor; nucleic acid binding
VDR	Transcription factor; receptor; nucleic acid binding
SOD1	Oxidoreductase
ESR2	Transcription factor; receptor; nucleic acid binding
HMOX1	Oxidoreductase
IGF1R	Null
MAPK14	Transferase; kinase
TNFRSF1A	Receptor
ABL1	Transferase; kinase
ALDH2	Oxidoreductase
MAPK1	Transferase; kinase
FGFR1	Null
HSD11B1	Oxidoreductase
ADH1C	Oxidoreductase
HGF	Protease; enzyme modulator; hydrolase; signaling molecule; calcium-binding protein; receptor
APAF1	Null
SIRT2	Nucleic acid binding; hydrolase
SULT2A1	Transferase
FGFR2	Null
BRAF	Transferase; kinase
HRAS	Enzyme modulator
ALB	Transfer/carrier protein
INS	Null
IMPA1	Phosphatase; hydrolase
HSD17B4	Null
HDAC8	Oxidoreductase; hydrolase; nucleic acid binding
IMPA2	Phosphatase; hydrolase
INSR	Null
POR	Null
PPIB	Isomerase
F2	Protease; hydrolase
RBP4	Transfer/carrier protein

Gene name

Protein class

TNF

Signaling molecule

COMT

Transferase

NR3C1

Transcription factor; receptor; nucleic acid binding

MAOA

Transferase; oxidoreductase; nucleic acid binding

TPH1

Null

AKT1

Transfer/carrier protein; transferase; calcium-binding protein; kinase

NTRK2

Null

GSK3B

Transferase; kinase

NR3C2

Transcription factor; receptor; nucleic acid binding

PON1

Null

IL4

Signaling molecule

CASP3

Protease; enzyme modulator; hydrolase

DPP4

Protease; enzyme modulator; hydrolase

PPARG

Transcription factor; receptor; nucleic acid binding

ADH1B

Oxidoreductase

MAOB

Transferase; oxidoreductase; nucleic acid binding

MTHFD1

Ligase

ESR1

Transcription factor; receptor; nucleic acid binding

VDR

Transcription factor; receptor; nucleic acid binding

SOD1

Oxidoreductase

ESR2

Transcription factor; receptor; nucleic acid binding

HMOX1

Oxidoreductase

IGF1R

Null

MAPK14

Transferase; kinase

TNFRSF1A

Receptor

ABL1

Transferase; kinase

ALDH2

Oxidoreductase

MAPK1

Transferase; kinase

FGFR1

Null

HSD11B1

Oxidoreductase

ADH1C

Oxidoreductase

HGF

Protease; enzyme modulator; hydrolase; signaling molecule; calcium-binding protein; receptor

APAF1

Null

SIRT2

Nucleic acid binding; hydrolase

SULT2A1

Transferase

FGFR2

Null

BRAF

Transferase; kinase

HRAS

Enzyme modulator

ALB

Transfer/carrier protein

INS

Null

IMPA1

Phosphatase; hydrolase

HSD17B4

Null

HDAC8

Oxidoreductase; hydrolase; nucleic acid binding

IMPA2

Phosphatase; hydrolase

INSR

Null

POR

Null

PPIB

Isomerase

Protease; hydrolase

RBP4

Transfer/carrier protein

基于网络药理学的柴胡抗抑郁作用机制研究

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吴丹 ¹^,² , 高耀 ¹^,² , 向欢 ³ , 邢婕 ¹^,² , 韩雨梅 ³ , 秦雪梅 ¹^,²^,^* , 田俊生 ¹^,²^,^*

药学学报 | 研究论文·药理学 2018,53(2): 210-219

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药学学报 | 研究论文·药理学 2018, 53(2): 210-219

基于网络药理学的柴胡抗抑郁作用机制研究

全屏

吴丹¹^,², 高耀¹^,², 向欢³, 邢婕¹^,², 韩雨梅³, 秦雪梅¹^,²^,^*, 田俊生¹^,²^,^*

作者信息

1.山西大学中医药现代研究中心, 山西太原 030006

2.山西大学地产中药功效物质研究与利用山西省重点实验室, 山西太原 030006

3.山西大学体育学院, 山西太原 030006

通讯作者:

* 秦雪梅, Tel:86-351-7018379, E-mail:qinxm@sxu.edu.cn;

田俊生, Tel:86-351-7019297, E-mail:jstian@sxu.edu.cn

Exploration into mechanism of antidepressant of Bupleuri radix based on network pharmacology

Dan WU¹^,², Yao GAO¹^,², Huan XIANG³, Jie XING¹^,², Yu-mei HAN³, Xue-mei QIN¹^,²^,^*, Jun-sheng TIAN¹^,²^,^*

Affiliations

1. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China

2. Shanxi Key Laboratory of Active Constituents Research and Utilization of TCM, Shanxi University, Taiyuan 030006, China

3. School of Physical Education, Shanxi University, Taiyuan 030006, China

出版时间: 2018-02-12 doi: 10.16438/j.0513-4870.2017-0914

文章导航

摘要

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构建柴胡活性成分-作用靶点网络和蛋白相互作用网络，对靶点涉及的功能和通路进行分析，探讨柴胡抗抑郁的作用机制。通过TCMSP数据库、文献挖掘和本实验室已有研究获取柴胡主要活性成分，利用DRAR-CPI服务器、GeneCards和OMIM数据库预测和筛选柴胡活性成分抗抑郁的作用靶点。采用Cytoscape软件构建活性成分-作用靶点网络，采用String数据库和Cytoscape软件绘制蛋白相互作用网络，通过SystemsDock Web Site对成分与靶点进行分子对接验证。采用DAVID数据库对靶点进行GO及KEGG通路分析，通过DisGeNET数据库对靶点所属的类型进行归属。筛选得到柴胡15个活性成分，涉及50个作用靶点。网络分析结果表明，柴胡主要涉及细胞过程、代谢过程、对应激的应答等生物过程，通过调节PI3K-AKT、MAPK、Rap1、Ras、FoxO和neurotrophin等信号通路来发挥抗抑郁作用。本研究体现了柴胡多成分-多靶点-多途径的作用特点，为进一步开展柴胡抗抑郁作用机制的研究提供了新思路和新方法。

关键词

柴胡 / 抑郁症 / 网络药理学 / 分子对接 / 作用靶点 / 蛋白相互作用

Abstract

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This study was designed to explore the antidepressant mechanism of Bupleuri radix through establishing the active components-targets network and protein interactions network and analyzing the functions and pathways of targets. The main active ingredients of Bupleuri radix were obtained by TCMSP, literature study and the results of our own work. Based on the DRAR-CPI, GeneCards and OMIM were used to predict and screen the active components of Bupleuri radix. The Cytoscape software was used to construct the active components-targets network of Bupleuri radix. The protein interactions network was constructed using the String database and Cytoscape software. The relation of the main active ingredients and targets were validated by Systems Dock Web Site. The GO and KEGG pathways involved in the targets were analyzed by DAVID. Using DisGeNET database to attribute the type of targets. The results showed that 15 active components and 50 targets of Bupleuri radix were involved. The network results showed that the process of metabolism, regulation and response to stress were mainly involved, by adjusting the PI3K-AKT, MAPK, Rap1, Ras, FoxO, neurotrophin and other signaling pathways to play its antidepressant effect. This study reflects the characteristics of multicomponents-multi-targets and multi-pathways of Bupleuri radix, which provides new ideas and clues for further research on the mechanism of anti-depressive effects of Bupleuri radix.

Key words

Bupleuri radix / depression / network pharmacology / molecular docking / target / protein interaction

引用本文

吴丹, 高耀, 向欢, 邢婕, 韩雨梅, 秦雪梅, 田俊生. 基于网络药理学的柴胡抗抑郁作用机制研究. 药学学报, 2018 , 53 (2) : 210 -219 . DOI: 10.16438/j.0513-4870.2017-0914

Dan WU, Yao GAO, Huan XIANG, Jie XING, Yu-mei HAN, Xue-mei QIN, Jun-sheng TIAN. Exploration into mechanism of antidepressant of Bupleuri radix based on network pharmacology[J]. Acta Pharmaceutica Sinica, 2018 , 53 (2) : 210 -219 . DOI: 10.16438/j.0513-4870.2017-0914

正文

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抑郁症为一种常见的情感性精神疾病, 具有高发病率、高复发率、高致残率等特点, 其临床主要表现为情绪低落、快感缺失、精力丧失, 世界卫生组织预言其将成为仅次于心脏病的第二大疾病负担^{[1, 2]}。目前, 全世界至少有20%的人受到抑郁症的困扰, 其中男性约为7%~12%, 女性约为20%~25%^[3]。在西方, 抑郁症的疾病负担预计到2030年将居于首位^[4], 在我国, 抑郁症的发病率约为3%^[5], 抑郁症的发生不仅降低了患者的生活质量, 同时给家庭和社会带来了的沉重的负担^[2]。抑郁症治疗的药物仍以化学药物为主, 但是一些抗抑郁西药有毒副作用、依从性较差, 而中医药注重整体调节, 毒副作用较少, 对抑郁症的疗效越来越受到重视, 特别是具有疏肝解郁作用的中药柴胡及其复方(如逍遥散、丹栀逍遥散、小柴胡汤、柴胡舒肝散、柴胡加龙骨牡蛎汤等)在临床上广泛使用并取得了较好的效果^[6]。

柴胡(Bupleuri radix)为伞形科植物柴胡(Bupleurum chinense DC.)或狭叶柴胡(Bupleurum scorzonerifolium Willd.)的干燥根, 辛、苦, 微寒; 归肝、胆、肺经; 具有疏散退热、舒肝解郁、升举阳气等作用^[7]。柴胡主要成分包括柴胡皂苷和黄酮类等。一般认为柴胡皂苷A和D为其抗抑郁的主要有效活性成分^[8], 但其结构不稳定, 在煎煮或炮制的过程中易转化为柴胡皂苷B1、B2, 且仍具有较好的生理活性^{[9, 10]}。柴胡中的黄酮类成分主要为黄酮醇, 如山奈酚(kaempferol)、槲皮素(quercetin)、异鼠李素(isorhamnetin)等, 文献报道均具有抗抑郁作用^{[8, 11-13]}。此外, 本课题组前期从柴胡中分离得到的8个多炔化合物在体外单胺类神经递质再摄取抑制实验中, 表现出明显的抗抑郁活性^[14-16]。

2007年Hopkins等提出了“网络药理学”的概念, 通过分析药物对疾病网络的干预, 构建“药物-靶点-疾病”网络, 为药物研发提供了新的策略^{[17, 18]}。中药因其成分复杂、系统庞大而不易研究, 网络药理学则为复杂中药系统的研究提供了新的思路和视角^[19]。Ding等^[20]采用蛋白相互作用网络对肾小球病的关键细胞骨架组分进行了预测。Zhang等^[21]通过网络药理学方法对乌头汤治疗类风湿关节炎的关键靶标进行了预测。Chen等^[22]通过网络药理学方法对复方柴归方超临界CO₂萃取组分抗抑郁作用机制进行了预测。Zhang等^[23]通过DRAR-CPI结合文本挖掘对交泰丸抗抑郁作用靶点进行预测, 采用DAVID数据库进行生物功能和通路分析, 探讨了交泰丸的抗抑郁机制。网络药理学研究策略的整体性、系统性与中医学从整体、辨证论治的角度诊治疾病的理论以及中药及其复方的多成分、多途径、多靶点协同作用的原理不谋而合^[24]。

本文采用网络药理学方法从整体性的角度对柴胡的抗抑郁作用机制进行探讨, 为深入研究柴胡及含柴胡的中药复方的抗抑郁作用提供了参考依据。

材料与方法

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化学成分的获取与活性成分的筛选 从TCMSP数据库(http://lsp.nwu.edu.cn/, Version 2.3)中获取柴胡的化学成分。根据柴胡中的化合物含量、相关生物功能(抗抑郁作用)、研究热度并结合本实验室前期的研究基础, 通过大量文献挖掘与整理获取已报道的柴胡的抗抑郁活性成分。

活性成分作用靶点的获取 将上述柴胡活性成分在Chembiodraw Ultra 12.0软件中绘制出各自的结构图, 并以mol2格式存储。利用PubChem (https://pubchem.ncbi.nlm.nih.gov/)、TCMSP数据库、ChemicalBook (http://www.chemicalbook.com/)对其分子结构进一步确证。

DRAR-CPI (http://cpi.bio-x.cn/drar, update in 2017-7-26)为一种基于反向分子对接的服务器, 它可以将药物分子和蛋白的三维结构特征进行对接, 用基于蛋白-配体相互作用的亲合性打分函数进行打分并排序, 预测出药物的潜在作用靶点^[25]。Z-score代表成分与蛋白相互作用的强度, 该服务器建议选取Z-score < -0.5为潜在靶点, 因此, 登陆DRAR-CPI服务器上传柴胡活性成分的mol2格式文件, 选取Z-score < -0.5为柴胡的潜在作用靶点。利用UniProt数据库的UniProt KB (http://www.uniprot.org/uniprot/, update in 2017-6-22)搜索功能, 导入柴胡蛋白靶点的PDB ID号, 限定物种为人, 经过检索和转化操作得到柴胡活性成分的基因靶点。

抑郁症相关作用靶点的筛选 通过在GeneCards数据库(http://www.genecards.org/, Version 4.5.0)和OMIM数据库(http://www.ncbi.nlm.nih.gov/omim, update in 2017-7-23)中输入关键词depression、depressive、depressed和antidepressant搜索已报道的、与抑郁症相关的基因, 去除重复基因和假阳性基因, 与上述作用靶点进行匹配, 得到柴胡活性成分抗抑郁的潜在作用靶点。

成分-作用靶点网络构建与分析 将柴胡的活性成分和抗抑郁作用靶点导入Cytoscape Version 3.4.0软件, 构建柴胡活性成分-作用靶点网络。

蛋白相互作用网络构建与分析 String数据库(https://string-db.org/, Version 10.5)^[26]是一种包含已知和预测的蛋白质-蛋白质相互作用的数据库, 其中收集了大量的蛋白相互作用关系, 共涉及9 643 763个蛋白, 1 380 838 440个相互作用, 包括实验检测得到的和通过生物信息学方法预测得到的数据。将柴胡的蛋白靶点导入String数据库, 限定物种为人, 获取蛋白相互作用关系, 结果保存成TSV格式, 保留文件中node1、node2和Combined score信息并导入Cytoscape软件绘制相互作用网路, 并对网络进行分析(Cytoscape→Tools→Network analyzer→Network analysis→Analyze network), 保存网络分析结果, 使用Cytoscape中的Generate style from statistics工具(Cytoscape→Tools→Network analyzer→Network analysis→Generate style from statistics)将节点大小和颜色设置用于反映Degree的大小, 边的粗细设置用于反映Combine score的大小, 获得最终的蛋白相互作用网络。

分子对接 Systems Dock Web Site是一个基于网络药理学预测和分析的网络服务器, 可以用于说明配体如何作用于复杂的分子网络。它通过DocK-IN评分的分子对接功能评估蛋白质-配体结合潜力^[27]。采用Systems Dock Web Site (http://systemsdock.unit.oist.jp, Version 2.0)对相互作用网络中Degree值靠前的5个分子与柴胡的活性成分进行分子对接验证。保存分子对接结果, 并对其Docking Score进行分析, 用以评价柴胡活性成分与靶点之间的结合活性。

生物过程与通路分析 生物学信息注释数据库(DAVID, https://david.ncifcrf.gov/, Version 6.8)为大规模的基因或蛋白提供系统综合的生物功能注释信息, 能够找出最显著富集的生物学注释^[28]。将柴胡的作用靶点导入DAVID数据库, Select Identifier设置为OFFICIAL GENE SYMBOL, List Type设置为Gene List, 限定物种为人, 对柴胡作用靶点进行GO分析和KEGG通路分析, 保存结果。设定阈值P < 0.05, 并按照涉及的靶点数目多少进行排序, 筛选排名靠前的生物过程或通路, 用GraphPad Prism 5.0软件绘图。

作用靶点类型归属 DisGeNET数据库(http://www.disgenet.org/web/DisGeNET/menu, Version 5.0)是包含与人类疾病相关的基因和变体的平台之一。在基因和疾病关系中, 该数据库一方面可以通过输入基因获取该基因相关的疾病信息, 另一方面还可以通过输入疾病获取与该疾病相关的基因信息。在DisGeNET数据库中选用基因进行检索, 将上述柴胡的作用靶点依次导入数据库中, 获取靶点类型信息(Protein Class)。

通路图绘制 利用UniProt数据库的UniProt KB搜索功能分别获取柴胡50个抗抑郁靶点的Uniprot ID。利用KEGG数据库(http://www.kegg.jp/) KEGG mapping中的KEGG Mapper工具, 将上述柴胡的UniProt ID导入, 限定物种为人, 获取柴胡抗抑郁作用的通路图, 筛选靠前的几条通路并进行整合绘制最终的通路图。

结果

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1 柴胡活性成分的筛选

TCMSP数据库获得柴胡化学成分349个, 经大量文献挖掘与整理, 根据柴胡各成分的含量、生物学功能、研究热度结合本实验室的研究筛选出具有抗抑郁作用的活性成分15个, 除了8个多炔类成分外, 其余在TCMSP数据库中均有收录。分别为山奈酚、异鼠李素、槲皮素、柴胡皂苷B2、柴胡皂苷B1、柴胡皂苷D、柴胡皂苷A及8个柴胡多炔, 详见表 1。

2 靶点预测

柴胡的15个活性成分在DRAR-CPI服务器中Z-score < -0.5的靶点共有1 131个, 去除重复后得到265个靶点。通过向Uniprot数据库UniProt KB搜索功能中输入蛋白靶点的PDB ID, 共得到264个基因靶点。通过与GeneCards和OMIM数据库中与抑郁症相关的基因进行比对, 筛选出50个可能与柴胡治疗抑郁症相关的作用靶点, 详见表 2。

3 活性成分-作用靶点网络构建

将柴胡活性成分和作用靶点的信息导入Cytoscape软件构建活性成分-作用靶点网络, 详见图 1。图中共涉及65个节点, 561个边。不同颜色和形状的节点分别代表柴胡潜在活性成分和靶点, 蓝色矩形节点代表作用靶点, 绿色菱形节点代表柴胡的活性成分, 边代表活性成分和作用靶点间的相互关联。从图中可看出同一靶点可对应于不同的活性成分, 也可对应于相同的活性成分, 充分体现了柴胡多成分、多靶点的作用特点。

4 蛋白相互作用网络构建与分析

将上述作用靶蛋白导入String数据库, 限定物种为人, 获取蛋白相互作用关系, 保存其TSV格式文件, 导入Cytoscape软件绘制相互作用网络, 详见图 2。图中节点表示蛋白, 边表示蛋白之间的关联, 共涉及48个节点, 281个边(其中ADH1C未在数据库中找到, PPIB与其他蛋白没有相互作用, 这两个蛋白不在相互作用网络中体现)。节点的大小和颜色表示Degree值的大小, 节点越大, 颜色由绿变红对应的Degree值越大。边的粗细表示Combine score, 边越粗Combine score值越大。

5 分子对接

上述相互作用网络中Degree表示某个蛋白具有相互作用的蛋白的数目。一般而言, 在一个网络中, 只有少数的节点具有很高的Degree, 这些节点为“中枢节点”, 在整个网络中占据重要的地位。也就是说, 在蛋白相互作用网络中筛选出的Degree排名靠前的靶蛋白在柴胡抗抑郁过程中发挥着重要的作用。对上述Degree数值排名前5位的重要靶点(表 3)进行分子对接验证。将其PDB ID号导入Systems Dock Web Site分子对接软件并与柴胡的15个成分进行对接, 对接结果详见表 4。分子对接结果显示, Docking Score值大于7.0的有2个(3.3%), 介于7.0~5.0之间的有18个(30%), 介于5.0~4.25之间的有28个(46.7%), 小于4.25的有12个(20%)。一般认为Docking Score值在4.25以上时表示分子与靶点之间有一定的结合活性, 大于5.0表明分子与靶点有较好的结合活性, 大于7.0则说明具有强烈的结合活性^[29]。分子对接结果表明, 柴胡15个活性成分与重要靶点的结合活性较好。

6 基因功能与通路分析

使用DAVID数据库对柴胡活性成分对应靶点进行GO和KEGG分析, 设定阈值P < 0.05, 并筛选靠前的生物过程或通路, 用GraphPad Prism 5.0绘图, 详见图 3~6。

GO富集分析指在某一功能层次上统计蛋白或者基因的数目组成的一个有向无环图, 包括生物过程(biological process, BP)、分子功能(molecular function, MF)和细胞组分(cellular component, CC) 3个分支。其中, BP分析(图 3)中排名靠前的有single-organism process (50个靶点/100%)、metabolic process (50个靶点/100%)、organic substance metabolic process (50个靶点/100%)、primary metabolic process (45个靶点/90%)、biological regulation (45个靶点/90%)。CC分析(图 4)中排名靠前的有cell (50个靶点/100%)、cell part (50个靶点/100%)、intracellular (49个靶点/98%)、intracellular part (49个靶点/98%)。MF分析(图 5)中排名靠前的有protein binding (44个靶点/88%)、catalytic activity (36个靶点/72%)、heterocyclic compound binding (28个靶点/56%)。通路分析结果如图 6所示, 柴胡抗抑郁的靶点主要涉及PI3K-AKT (11个靶点/22%)、MAPK (11个靶点/22%)、Rap1 (11个靶点/22%)、Ras (10个靶点/20%)、FoxO (8个靶点/16%)、neurotrophin (8个靶点/16%)等信号通路。

7 作用靶点类型归属

将柴胡的50个作用靶点依次导入DisGeNET数据库, 获取靶点对应的类型, 详见表 5。结果表明柴胡抗抑郁过程中有信号分子、转录因子、受体、蛋白(转运蛋白、载体蛋白、钙结合蛋白等)、酶(氧化还原酶、激酶、磷酸酶、水解酶等)等物质的参与。

8 靶点通路分析图

利用KEGG Mapper工具获取柴胡抗抑郁作用的通路图, 筛选靠前的几条通路并进行整合绘制最终的通路图(图 7)。图中箭头表示促进作用, T-箭头表示抑制作用, 不同颜色箭头表示不同的通路。通路靶点标记为浅蓝色, 柴胡抗抑郁靶点标记为深蓝色。图中显示出了PI3K-AKT、MAPK、Rap1、Ras、FoxO和neurotrophin信号通路, 涉及19个柴胡的抗抑郁靶点(占柴胡抗抑郁靶点的38%)。提示柴胡抗抑郁靶点分散于这几条通路中, 通过调节其中的几个环节发挥作用, 绝大多数靶点在多条通路中发挥作用, 如Ras、B-Raf、AKT和ABL等。

讨论

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柴胡具有疏肝解郁作用, 是治疗郁证的要药, 以其为主要药物的复方在抑郁症治疗中占了绝大比例, 因此, 柴胡的抗抑郁机制的研究具有重要意义。

柴胡中的山奈酚、异鼠李素、槲皮素、柴胡皂苷D、柴胡皂苷A及8个多炔成分均为已报道的具有抗抑郁作用的活性成分。其中柴胡皂苷D和A不稳定, 容易转化成柴胡皂苷B1、B2。Liu等^[30]研究表明, 柴胡饮片经水煎煮后柴胡皂苷B2大幅度增加, 柴胡皂苷A和D逐渐减少, 本实验室^[31]前期研究表明柴胡醋制后皂苷A和D的含量下降, B1和B2的含量升高, 醋制后保肝作用优于生品, 肝肾毒性略低于生品, 提示可能是B1、B2发挥了作用, 因此, 在本研究中将柴胡皂苷B1、B2考虑在内。网络分析结果显示柴胡皂苷B1、B2连接的靶点数目分别为13、10, 且与重要靶点的分子对接结果均大于5, 提示柴胡皂苷B1、B2可能具有抗抑郁作用。

成分靶点网络显示了柴胡多成分、多靶点的抗抑郁作用特点。蛋白相互作用网络结果显示柴胡靶蛋白间存在着相互关系, 是一个复杂交互的网络而并非单独起作用。分子对接结果显示15个成分与重要靶蛋白之间存在较好的结合活性, 为后续的网络分析奠定了好的基础。

靶点GO分析和靶点归属分析结果表明, 柴胡治疗抑郁症涉及细胞过程、代谢过程和对应激的应答等生物过程, 涉及细胞器、细胞膜和细胞质等细胞组分, 涉及小分子、阳离子、金属离子等分子, 有信号分子、转录因子、受体、蛋白和酶等多种物质的参与, 是一个复杂的过程。靶点通路分析结果显示, 柴胡抗抑郁的靶点主要涉及PI3K-AKT、MAPK、Rap1、Ras、FoxO和neurotrophin等信号通路。

神经营养因子(NTF)是一类由神经支配的组织和星形胶质细胞产生的对中枢和外周神经系统均有营养活性的蛋白, 在抑郁症的发病中也发挥了重要作用, 其中BDNF的研究较多^[32]。通路图中显示, 柴胡通过影响神经营养因子(BDNF、NGF和NT3/4)的受体发挥作用。

PI3K-AKT信号通路广泛存在于细胞中, 是介导多种生长因子促存活的重要通路^[33], 该通路在抑郁症的发生中, 为一个连接神经递质和抑郁症状的重要纽带。通路图中显示PI3K-AKT通路与Rap1、Ras、FoxO、neurotrophin通路均有关联, 提示该通路在柴胡发挥抗抑郁过程中发挥纽带作用。MAPK信号转导通路存在于大多数细胞内, 在细胞增殖、分化、转化及凋亡等过程中具有重要的作用^[34], 其中ERKl/2通路与抑郁症关系最为密切。在通路图中已显示柴胡对ERK的作用。Ras基因编码一种膜结合型的GTP/GDP结合蛋白, 在进化中相当保守, 广泛存在于各种真核生物, 具有重要的生理功能。Ras相关信号通路功能异常与抗抑郁治疗、抑郁状态、神经可塑性及神经营养因子均有很强的相关性, 在细胞内信号通路调节中起着至关重要的作用^[35]。Rap属于Ras家族, 含有Rap1和Rap2两个亚类。通路图中显示, Ras和Rap1通路与PI3K-AKT、MAPK、FoxO、neurotrophin信号通路均有关联。提示Ras和Rap1通路在柴胡抗抑郁过程中发挥纽带作用。FoxO家族是Fox基因家族中的一个亚族, 为细胞核内一种转录因子, 参与调节细胞增殖、分化和凋亡等过程^[36]。5-羟色胺可通过影响FoxO3a的活化调节应激状态^[37], FoxO3a基因缺陷型小鼠表现出抑郁样行为^[38], 表明FoxO3a与抑郁症有紧密关联。靶点通路分析图中显示, 柴胡可作用于FoxO相关的受体/蛋白发挥作用。

综上所述, 网络药理结果显示柴胡的15个活性成分作用于50个靶点, 涉及多种过程、分子和通路, 体现了柴胡多成分-多靶点-多途径的作用特点, 上述结果与文献报道基本一致。本文通过蛋白相互作用网络预测了柴胡抗抑郁作用的5个重要靶蛋白, 并对其进行了分子对接验证, 一方面从某种程度上验证了DRAR-CPI预测靶点的可靠性, 另一方面为后续进一步验证奠定了基础。此外, 本文还对作用靶点的位置进行了归属, 并绘制通路图, 提示PI3K-AKT信号通路、Ras和Rap1通路的枢纽作用, 对柴胡抗抑郁的机制进一步研究提供了方向, 相关的靶点验证实验正在进行中。

基金

收起

中国博士后科学基金面上资助项目(2016M602414)
山西省科技重点研发计划(201603D3113013)
山西省科技重点研发计划(201603D321077)
山西省科技重点研发计划(201701D22111344)
地产中药功效物质研究与利用山西省重点实验室项目(201605D111004)
山西省科技创新重点团队项目(201605D131045-18)

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2018年第53卷第2期

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文章信息

doi: 10.16438/j.0513-4870.2017-0914

接收时间：2017-09-14
首发时间：2026-01-15
出版时间：2018-02-12

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文章信息

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出版历史

收稿日期：2017-09-14
修回日期：2017-10-16

基金

中国博士后科学基金面上资助项目(2016M602414)

山西省科技重点研发计划(201603D3113013)

山西省科技重点研发计划(201603D321077)

山西省科技重点研发计划(201701D22111344)

地产中药功效物质研究与利用山西省重点实验室项目(201605D111004)

山西省科技创新重点团队项目(201605D131045-18)

作者信息

1.山西大学中医药现代研究中心, 山西太原 030006

2.山西大学地产中药功效物质研究与利用山西省重点实验室, 山西太原 030006

3.山西大学体育学院, 山西太原 030006

通讯作者:

* 秦雪梅, Tel:86-351-7018379, E-mail:qinxm@sxu.edu.cn;

田俊生, Tel:86-351-7019297, E-mail:jstian@sxu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

NO.	Name	Chemical formula
1	Isorhamnetin	C₁₆H₁₂O₇
2	Quercetin	C₁₅H₁₀O₇
3	Kaempferol	C₁₅H₁₀O₆
4	Saikosaponin D	C₄₂H₆₈O₁₃
5	Saikosaponin B1	C₄₂H₆₈O₁₃
6	Saikosaponin B2	C₄₂H₆₈O₁₃
7	Saikosaponin A	C₄₂H₆₈O₁₃
8	D1	C₁₅H₁₈O
9	D2	C₁₅H₁₈O
10	D3	C₁₇H₂₂O
11	D4	C₁₇H₂₂O
12	D5	C₁₅H₁₈O
13	D6	C₁₇H₂₀O₂
14	D7	C₁₇H₂₀O₂
15	D8	C₁₇H₂₂O

NO.

Name

Chemical formula

Isorhamnetin

C₁₆H₁₂O₇

Quercetin

C₁₅H₁₀O₇

Kaempferol

C₁₅H₁₀O₆

Saikosaponin D

C₄₂H₆₈O₁₃

Saikosaponin B1

C₄₂H₆₈O₁₃

Saikosaponin B2

C₄₂H₆₈O₁₃

Saikosaponin A

C₄₂H₆₈O₁₃

C₁₅H₁₈O

C₁₇H₂₂O

C₁₅H₁₈O

C₁₇H₂₀O₂

C₁₇H₂₂O

NO.	PDB ID	Target
1	1A8M	TNF
2	3BWY	COMT
3	1P93	NR3C1
4	2Z5X	MAOA
5	1MLW	TPH1
6	3CQW	AKT1
7	1WWB	NTRK2
8	1J1B	GSK3B
9	2A3I	NR3C2
10	1V04	PON1
11	2CYK	IL4
12	1GFW	CASP3
13	2HHA	DPP4
14	1ZEO	PPARG
15	1HSZ	ADH1B
16	1GOS	MAOB
17	1DIA	MTHFD1
18	1R5K	ESR1
19	1E3G	AR
20	1DB1	VDR
21	2C9V	SOD1
22	1QKM	ESR2
23	1S8C	HMOX1
24	2OJ9	IGF1R
25	1A9U	MAPK14
26	1FT4	TNFRSF1A
27	1OPL	ABL1
28	1OF7	ALDH2
29	1TVO	MAPK1
30	2FGI	FGFR1
31	1XU9	HSD11B1
32	1HT0	ADH1C
33	1GMN	HGF
34	1Z6T	APAF1
35	1J8F	SIRT2
36	1J99	SULT2A1
37	2PVY	FGFR2
38	1UWJ	BRAF
39	5P21	HRAS
40	2BX8	ALB
41	1TYL	INS
42	1IMB	IMPA1
43	1ZBQ	HSD17B4
44	1W22	HDAC8
45	2CZH	IMPA2
46	2AUH	INSR
47	1B1C	POR
48	1CYN	PPIB
49	1A3B	F2
50	1QAB	RBP4

NO.

PDB ID

Target

1A8M

TNF

3BWY

COMT

1P93

NR3C1

2Z5X

MAOA

1MLW

TPH1

3CQW

AKT1

1WWB

NTRK2

1J1B

GSK3B

2A3I

NR3C2

1V04

PON1

2CYK

IL4

1GFW

CASP3

2HHA

DPP4

1ZEO

PPARG

1HSZ

ADH1B

1GOS

MAOB

1DIA

MTHFD1

1R5K

ESR1

1E3G

1DB1

VDR

2C9V

SOD1

1QKM

ESR2

1S8C

HMOX1

2OJ9

IGF1R

1A9U

MAPK14

1FT4

TNFRSF1A

1OPL

ABL1

1OF7

ALDH2

1TVO

MAPK1

2FGI

FGFR1

1XU9

HSD11B1

1HT0

ADH1C

1GMN

HGF

1Z6T

APAF1

1J8F

SIRT2

1J99

SULT2A1

2PVY

FGFR2

1UWJ

BRAF

5P21

HRAS

2BX8

ALB

1TYL

INS

1IMB

IMPA1

1ZBQ

HSD17B4

1W22

HDAC8

2CZH

IMPA2

2AUH

INSR

1B1C

POR

1CYN

PPIB

1A3B

1QAB

RBP4

NO.	Degree	PDB ID	Target name
1	34	2BX8	ALB
2	32	1TYL	INS
3	25	1A8M	TNF
4	25	3CQW	AKT1
5	25	1TVO	MAPK1

NO.

Degree

PDB ID

Target name

2BX8

ALB

1TYL

INS

1A8M

TNF

3CQW

AKT1

1TVO

MAPK1

Target name	PDB ID	Ingredient	Docking score
AKT1	3CQW	Isorhamnetin	3.679
ALB	2BX8	Isorhamnetin	3.112
INS	1TYL	Isorhamnetin	2.944
MAPK1	1TVO	Isorhamnetin	2.465
TNF	1A8M	Isorhamnetin	3.099
AKT1	3CQW	Kaempferol	6.604
ALB	2BX8	Kaempferol	5.064
INS	1TYL	Kaempferol	5.248
MAPK1	1TVO	Kaempferol	7.877
TNF	1A8M	Kaempferol	6.709
AKT1	3CQW	Quercetin	6.636
ALB	2BX8	Quercetin	4.812
INS	1TYL	Quercetin	5.106
MAPK1	1TVO	Quercetin	7.888
TNF	1A8M	Quercetin	6.574
ALB	2BX8	Saikosaponin D	6.804
TNF	1A8M	Saikosaponin D	5.054
AKT1	3CQW	Saikosaponin B2	5.907
ALB	2BX8	Saikosaponin B2	6.823
ALB	2BX8	Saikosaponin B1	6.828
AKT1	3CQW	D8	5.16
ALB	2BX8	D8	4.833
INS	1TYL	D8	4.674
MAPK1	1TVO	D8	4.716
TNF	1A8M	D8	5.172
AKT1	3CQW	D7	5.034
ALB	2BX8	D7	4.856
INS	1TYL	D7	4.415
MAPK1	1TVO	D7	4.224
TNF	1A8M	D7	4.706
AKT1	3CQW	D6	5.042
ALB	2BX8	D6	4.731
INS	1TYL	D6	4.411
MAPK1	1TVO	D6	4.344
TNF	1A8M	D6	4.732
AKT1	3CQW	D5	4.492
ALB	2BX8	D5	4.402
INS	1TYL	D5	4.081
MAPK1	1TVO	D5	4.083
TNF	1A8M	D5	4.312
AKT1	3CQW	D4	5.159
ALB	2BX8	D4	4.96
INS	1TYL	D4	4.633
MAPK1	1TVO	D4	4.714
TNF	1A8M	D4	4.964
AKT1	3CQW	D3	4.954
ALB	2BX8	D3	4.75
INS	1TYL	D3	4.635
MAPK1	1TVO	D3	4.712
TNF	1A8M	D3	5.154
AKT1	3CQW	D2	4.55
ALB	2BX8	D2	4.343
INS	1TYL	D2	4.078
MAPK1	1TVO	D2	4.082
TNF	1A8M	D2	4.264
AKT1	3CQW	D1	4.319
ALB	2BX8	D1	4.531
INS	1TYL	D1	4.044
MAPK1	1TVO	D1	4.084
TNF	1A8M	D1	4.491

Target name

PDB ID

Ingredient

Docking score

AKT1

3CQW

Isorhamnetin

3.679

ALB

2BX8

Isorhamnetin

3.112

INS

1TYL

Isorhamnetin

2.944

MAPK1

1TVO

Isorhamnetin

2.465

TNF

1A8M

Isorhamnetin

3.099

AKT1

3CQW

Kaempferol

6.604

ALB

2BX8

Kaempferol

5.064

INS

1TYL

Kaempferol

5.248

MAPK1

1TVO

Kaempferol

7.877

TNF

1A8M

Kaempferol

6.709

AKT1

3CQW

Quercetin

6.636

ALB

2BX8

Quercetin

4.812

INS

1TYL

Quercetin

5.106

MAPK1

1TVO

Quercetin

7.888

TNF

1A8M

Quercetin

6.574

ALB

2BX8

Saikosaponin D

6.804

TNF

1A8M

Saikosaponin D

5.054

AKT1

3CQW

Saikosaponin B2

5.907

ALB

2BX8

Saikosaponin B2

6.823

ALB

2BX8

Saikosaponin B1

6.828

AKT1

3CQW

5.16

ALB

2BX8

4.833

INS

1TYL

4.674

MAPK1

1TVO

4.716

TNF

1A8M

5.172

AKT1

3CQW

5.034

ALB

2BX8

4.856

INS

1TYL

4.415

MAPK1

1TVO

4.224

TNF

1A8M

4.706

AKT1

3CQW

5.042

ALB

2BX8

4.731

INS

1TYL

4.411

MAPK1

1TVO

4.344

TNF

1A8M

4.732

AKT1

3CQW

4.492

ALB

2BX8

4.402

INS

1TYL

4.081

MAPK1

1TVO

4.083

TNF

1A8M

4.312

AKT1

3CQW

5.159

ALB

2BX8

4.96

INS

1TYL

4.633

MAPK1

1TVO

4.714

TNF

1A8M

4.964

AKT1

3CQW

4.954

ALB

2BX8

4.75

INS

1TYL

4.635

MAPK1

1TVO

4.712

TNF

1A8M

5.154

AKT1

3CQW

4.55

ALB

2BX8

4.343

INS

1TYL

4.078

MAPK1

1TVO

4.082

TNF

1A8M

4.264

AKT1

3CQW

4.319

ALB

2BX8

4.531

INS

1TYL

4.044

MAPK1

1TVO

4.084

TNF

1A8M

4.491

Gene name	Protein class
TNF	Signaling molecule
COMT	Transferase
NR3C1	Transcription factor; receptor; nucleic acid binding
MAOA	Transferase; oxidoreductase; nucleic acid binding
TPH1	Null
AKT1	Transfer/carrier protein; transferase; calcium-binding protein; kinase
NTRK2	Null
GSK3B	Transferase; kinase
NR3C2	Transcription factor; receptor; nucleic acid binding
PON1	Null
IL4	Signaling molecule
CASP3	Protease; enzyme modulator; hydrolase
DPP4	Protease; enzyme modulator; hydrolase
PPARG	Transcription factor; receptor; nucleic acid binding
ADH1B	Oxidoreductase
MAOB	Transferase; oxidoreductase; nucleic acid binding
MTHFD1	Ligase
ESR1	Transcription factor; receptor; nucleic acid binding
AR	Transcription factor; receptor; nucleic acid binding
VDR	Transcription factor; receptor; nucleic acid binding
SOD1	Oxidoreductase
ESR2	Transcription factor; receptor; nucleic acid binding
HMOX1	Oxidoreductase
IGF1R	Null
MAPK14	Transferase; kinase
TNFRSF1A	Receptor
ABL1	Transferase; kinase
ALDH2	Oxidoreductase
MAPK1	Transferase; kinase
FGFR1	Null
HSD11B1	Oxidoreductase
ADH1C	Oxidoreductase
HGF	Protease; enzyme modulator; hydrolase; signaling molecule; calcium-binding protein; receptor
APAF1	Null
SIRT2	Nucleic acid binding; hydrolase
SULT2A1	Transferase
FGFR2	Null
BRAF	Transferase; kinase
HRAS	Enzyme modulator
ALB	Transfer/carrier protein
INS	Null
IMPA1	Phosphatase; hydrolase
HSD17B4	Null
HDAC8	Oxidoreductase; hydrolase; nucleic acid binding
IMPA2	Phosphatase; hydrolase
INSR	Null
POR	Null
PPIB	Isomerase
F2	Protease; hydrolase
RBP4	Transfer/carrier protein

Gene name

Protein class

TNF

Signaling molecule

COMT

Transferase

NR3C1

Transcription factor; receptor; nucleic acid binding

MAOA

Transferase; oxidoreductase; nucleic acid binding

TPH1

Null

AKT1

Transfer/carrier protein; transferase; calcium-binding protein; kinase

NTRK2

Null

GSK3B

Transferase; kinase

NR3C2

Transcription factor; receptor; nucleic acid binding

PON1

Null

IL4

Signaling molecule

CASP3

Protease; enzyme modulator; hydrolase

DPP4

Protease; enzyme modulator; hydrolase

PPARG

Transcription factor; receptor; nucleic acid binding

ADH1B

Oxidoreductase

MAOB

Transferase; oxidoreductase; nucleic acid binding

MTHFD1

Ligase

ESR1

Transcription factor; receptor; nucleic acid binding

VDR

Transcription factor; receptor; nucleic acid binding

SOD1

Oxidoreductase

ESR2

Transcription factor; receptor; nucleic acid binding

HMOX1

Oxidoreductase

IGF1R

Null

MAPK14

Transferase; kinase

TNFRSF1A

Receptor

ABL1

Transferase; kinase

ALDH2

Oxidoreductase

MAPK1

Transferase; kinase

FGFR1

Null

HSD11B1

Oxidoreductase

ADH1C

Oxidoreductase

HGF

Protease; enzyme modulator; hydrolase; signaling molecule; calcium-binding protein; receptor

APAF1

Null

SIRT2

Nucleic acid binding; hydrolase

SULT2A1

Transferase

FGFR2

Null

BRAF

Transferase; kinase

HRAS

Enzyme modulator

ALB

Transfer/carrier protein

INS

Null

IMPA1

Phosphatase; hydrolase

HSD17B4

Null

HDAC8

Oxidoreductase; hydrolase; nucleic acid binding

IMPA2

Phosphatase; hydrolase

INSR

Null

POR

Null

PPIB

Isomerase

Protease; hydrolase

RBP4

Transfer/carrier protein