药学学报

No.	Compound	MW/g·mol^-1
Salvia miltiorrhiza
DS1	Trijuganone B	280.34
DS2	Poriferasterol	412.77
DS3	Clionasterol	414.79
DS4	Isoimperatorin	270.30
DS5	Sugiol	300.48
DS6	Dehydrotanshinone Ⅱ A	292.35
DS7	Baicalin	446.39
DS8	Digallic acid	322.24
DS9	α-Amyrin	426.80
DS10	Arucadiol	298.41
DS11	2-Isopropyl-8-methylphenanthrene-3, 4-dione	264.34
DS12	3α-Hydroxytanshinone Ⅱ A	310.37
DS13	Tournefolic acid A	312.29
DS14	4-Methylenemiltirone	266.36
DS15	2-(4-Hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-7-methoxy-3-benzofurancarboxaldehyde	356.40
DS16	6-o-Syringyl-8-o-acetyl shanzhiside methyl ester	628.64
DS17	Formyltanshinone	290.28
DS18	3-β-Hydroxymethyllenetanshiquinone	294.32
DS19	Methylenetanshinquinone	278.32
DS20	Przewalskin A	398.49
DS21	Przewalskin B	330.46
DS22	Przewaquinone B	292.30
DS23	Przewaquinone C	296.34
DS24	(6S, 7R)-6, 7-Dihydroxy-1, 6-dimethyl-8, 9-dihydro-7H-naphtho[8, 7-g]benzofuran-10, 11-dione	312.34
DS25	Przewaquinone F	312.34
DS26	Sclareol	308.56
DS27	Tanshinaldehyde	308.35
DS28	Danshenol B	354.48
DS29	Danshenol A	336.41
DS30	Salvilenone	292.40
DS31	Cryptotanshinone	296.39
DS32	Dan-shexinkum D	336.41
DS33	Danshenspiroketallactone	282.36
DS34	Deoxyneocryptotanshinone	298.41
DS35	Dihydrotanshinlactone	266.31
DS36	Dihydrotanshinone Ⅰ	278.32
DS37	Epidanshenspiroketallactone	284.38
DS38	Ferruginol	286.50
DS39	Isocryptotanshi-none	296.39
DS40	Isotanshinone Ⅱ A	294.37
DS41	Manool	290.50
DS42	Microstegiol	298.46
DS43	Miltionone Ⅰ	312.39
DS44	Miltionone Ⅱ	312.39
DS45	Miltipolone	300.43
DS46	Miltirone	282.41
DS47	Miltirone Ⅱ	272.32
DS48	Neocryptotanshinone Ⅱ	270.35
DS49	Neocryptotanshinone	314.41
DS50	Nortanshinone	280.29
DS51	Prolithospermic acid	314.31
DS52	(2R)-3-(3, 4-Dihydroxyphenyl)-2-[(Z)-3-(3, 4-dihydroxyphenyl)acryloyl]oxy-propionic acid	360.34
DS53	(Z)-3-[2-[(E)-2-(3, 4-Dihydroxyphenyl)vinyl]-3, 4-dihydroxy-phenyl]acrylic acid	314.31
DS54	Salvianolic acid G	340.30
DS55	Salvianolic acid J	538.49
DS56	Salvilenone Ⅰ	270.40
DS57	Salviolone	268.38
DS58	Tanshindiol A	312.34
DS59	Tanshindiol B	312.34
DS60	Przewaquinone E	312.34
DS61	Tanshinone Ⅱ A	294.37
DS62	Tanshinone Ⅱ B	310.37
DS63	Tanshinone Ⅵ	296.34
DS64	Salvianolic acid B	718.60
Ganoderma lucidum
LZ1	(+)-Ganoderic acid Mf	512.80
LZ2	(+)-Methyl ganolucidate A	514.77
LZ3	Methyl lucidenate F	470.66
LZ4	22, 23-Dimethylene ganodermic acid S	578.86
LZ5	22β-Acetoxy-3α, 15α-dihydroxylanosta-7, 9(11), 24-trien-26-oic acid	528.90
LZ6	Campesta-7, 22E-dien-3beta-ol	398.74
LZ7	5α-Lanosta-7, 9(11), 24-triene-15α, 26-dihydroxy-3-one	454.76
LZ8	Epoxyganoderiol A	472.78
LZ9	Epoxyganoderiol B	454.76
LZ10	Epoxyganoderiol C	456.78
LZ11	Ergosta-4, 6, 8(14), 22-tetraene-3-one	406.71
LZ12	Ergosta-4, 7, 22-trien-3, 6-dione	408.68
LZ13	Ergosta-7, 22-dien-3β-yl palmitate	637.20
LZ14	Ergosta-7, 22-dien-3β, 5α, 6α-triol	430.74
LZ15	Ergosta-7, 22-diene-3β-yl linoleate	661.22
LZ16	Ergosta-7, 22-diene-3β-yl palmitate	637.20
LZ17	Ergosta-7, 22-diene-3β-yl pentadecanoate	623.17
LZ18	Ergosta-7, 9(11), 22-trien-3β, 5α, 6α-triol	442.75
LZ19	Peroxyergosterol	428.72
LZ20	Ganoderal B	440.73
LZ21	Ganoderan B	454.76
LZ22	Ganoderic acid beta	500.74
LZ23	Ganoderic acid DM	468.74
LZ24	Ganodermic acid R	554.84
LZ25	Ganoderic acid Mi	528.85
LZ26	(E, 5S, 6S)-5-Acetoxy-6-[(3R, 5R, 10S, 13R, 14R, 17R)-3-hydroxy-4, 4, 10, 13, 14-pentamethyl-2, 3, 5, 6, 12, 15, 16, 17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylhept-2-enoic acid	512.80
LZ27	Ganoderic acid TQ	524.81
LZ28	Ganoderic acid TR	468.74
LZ29	Ganoderic acid Ⅴ	528.80
LZ30	Ganoderic acid Ⅴ1	512.75
LZ31	Ganoderic acid X	512.80
LZ32	Ganoderic acid Y	454.76
LZ33	Ganoderic acid Z	456.78
LZ34	Ganoderic aldehyde A	454.76
LZ35	Ganoderiol F	454.76
LZ36	Ganodermanondiol	456.78
LZ37	Ganodermatriol	456.78
LZ38	Ganodermenonol	438.76
LZ39	Ganodermic acid T-Q	512.80
LZ40	Ganodermic acid T-O	512.80
LZ41	Ganolucidic acid E	484.74
LZ42	Ganosporelactone B	530.72
LZ43	Lanosta-7, 9(11), 24-trien-15α-acetoxy-3α-hydroxy-23-oxo-26-oic acid	526.78
LZ44	Lanosta-7, 9(11), 24-trien-3α-acetoxy-15α-hydroxy-23-oxo-26-oic acid	526.78
LZ45	Lanosta-7, 9(11), 24-trien-3α-acetoxy-26-oic acid	496.80
LZ46	Lucialdehyde A	438.76
LZ47	Lucialdehyde B	452.74
LZ48	Lucialdehyde C	454.76
LZ49	Lucidenic acid A	458.65
LZ50	Lucidone A	402.58
LZ51	Lucidumol A	458.80
LZ52	Methyl ganoderic acid DM	482.77
LZ53	Methyl ganoderic acid TR	482.77
LZ54	Methyl lucidenate Q	474.70
LZ55	Cerevisterol	430.74
LZ56	Ergosta-7, 22E-dien-3β-ol	398.74
LZ57	Oleanic acid	456.70
Sedum sarmentosum Bunge
CP1	Liquiritigenin	256.27
CP2	Isorhamnetin	316.28
CP3	Sarmentosine	275.29
CP4	δ-Amyrone	424.70
CP5	Kaempferide	300.26
CP6	Sedumoside Ⅰ	388.50
CP7	Tricin	330.29
Polygoni Cuspidati Rhizoma et Radix
HZ1	6, 8-Dihydroxy-7-methoxyxanthone	258.24
HZ2	Physovenine	262.34
HZ3	Picralinal	366.45
HZ4	Physciondiglucoside	608.60
HZ5	Rhein	284.23
HZ6	Torachrysone-8-O-β-D-(6'-oxayl)-glucoside	480.46
HZ7	(+)-Catechin	290.29
HZ8	Resveratrol	228.26
HZ9	Polydatin	390.42
HZ10	Emodin	270.24
Multi-drug
A1	β-Sitosterol	414.79
A2	Luteolin	286.25
A3	Quercetin	302.25

No.	Compound	MW/g·mol^-1
Salvia miltiorrhiza
DS1	Trijuganone B	280.34
DS2	Poriferasterol	412.77
DS3	Clionasterol	414.79
DS4	Isoimperatorin	270.30
DS5	Sugiol	300.48
DS6	Dehydrotanshinone Ⅱ A	292.35
DS7	Baicalin	446.39
DS8	Digallic acid	322.24
DS9	α-Amyrin	426.80
DS10	Arucadiol	298.41
DS11	2-Isopropyl-8-methylphenanthrene-3, 4-dione	264.34
DS12	3α-Hydroxytanshinone Ⅱ A	310.37
DS13	Tournefolic acid A	312.29
DS14	4-Methylenemiltirone	266.36
DS15	2-(4-Hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-7-methoxy-3-benzofurancarboxaldehyde	356.40
DS16	6-o-Syringyl-8-o-acetyl shanzhiside methyl ester	628.64
DS17	Formyltanshinone	290.28
DS18	3-β-Hydroxymethyllenetanshiquinone	294.32
DS19	Methylenetanshinquinone	278.32
DS20	Przewalskin A	398.49
DS21	Przewalskin B	330.46
DS22	Przewaquinone B	292.30
DS23	Przewaquinone C	296.34
DS24	(6S, 7R)-6, 7-Dihydroxy-1, 6-dimethyl-8, 9-dihydro-7H-naphtho[8, 7-g]benzofuran-10, 11-dione	312.34
DS25	Przewaquinone F	312.34
DS26	Sclareol	308.56
DS27	Tanshinaldehyde	308.35
DS28	Danshenol B	354.48
DS29	Danshenol A	336.41
DS30	Salvilenone	292.40
DS31	Cryptotanshinone	296.39
DS32	Dan-shexinkum D	336.41
DS33	Danshenspiroketallactone	282.36
DS34	Deoxyneocryptotanshinone	298.41
DS35	Dihydrotanshinlactone	266.31
DS36	Dihydrotanshinone Ⅰ	278.32
DS37	Epidanshenspiroketallactone	284.38
DS38	Ferruginol	286.50
DS39	Isocryptotanshi-none	296.39
DS40	Isotanshinone Ⅱ A	294.37
DS41	Manool	290.50
DS42	Microstegiol	298.46
DS43	Miltionone Ⅰ	312.39
DS44	Miltionone Ⅱ	312.39
DS45	Miltipolone	300.43
DS46	Miltirone	282.41
DS47	Miltirone Ⅱ	272.32
DS48	Neocryptotanshinone Ⅱ	270.35
DS49	Neocryptotanshinone	314.41
DS50	Nortanshinone	280.29
DS51	Prolithospermic acid	314.31
DS52	(2R)-3-(3, 4-Dihydroxyphenyl)-2-[(Z)-3-(3, 4-dihydroxyphenyl)acryloyl]oxy-propionic acid	360.34
DS53	(Z)-3-[2-[(E)-2-(3, 4-Dihydroxyphenyl)vinyl]-3, 4-dihydroxy-phenyl]acrylic acid	314.31
DS54	Salvianolic acid G	340.30
DS55	Salvianolic acid J	538.49
DS56	Salvilenone Ⅰ	270.40
DS57	Salviolone	268.38
DS58	Tanshindiol A	312.34
DS59	Tanshindiol B	312.34
DS60	Przewaquinone E	312.34
DS61	Tanshinone Ⅱ A	294.37
DS62	Tanshinone Ⅱ B	310.37
DS63	Tanshinone Ⅵ	296.34
DS64	Salvianolic acid B	718.60
Ganoderma lucidum
LZ1	(+)-Ganoderic acid Mf	512.80
LZ2	(+)-Methyl ganolucidate A	514.77
LZ3	Methyl lucidenate F	470.66
LZ4	22, 23-Dimethylene ganodermic acid S	578.86
LZ5	22β-Acetoxy-3α, 15α-dihydroxylanosta-7, 9(11), 24-trien-26-oic acid	528.90
LZ6	Campesta-7, 22E-dien-3beta-ol	398.74
LZ7	5α-Lanosta-7, 9(11), 24-triene-15α, 26-dihydroxy-3-one	454.76
LZ8	Epoxyganoderiol A	472.78
LZ9	Epoxyganoderiol B	454.76
LZ10	Epoxyganoderiol C	456.78
LZ11	Ergosta-4, 6, 8(14), 22-tetraene-3-one	406.71
LZ12	Ergosta-4, 7, 22-trien-3, 6-dione	408.68
LZ13	Ergosta-7, 22-dien-3β-yl palmitate	637.20
LZ14	Ergosta-7, 22-dien-3β, 5α, 6α-triol	430.74
LZ15	Ergosta-7, 22-diene-3β-yl linoleate	661.22
LZ16	Ergosta-7, 22-diene-3β-yl palmitate	637.20
LZ17	Ergosta-7, 22-diene-3β-yl pentadecanoate	623.17
LZ18	Ergosta-7, 9(11), 22-trien-3β, 5α, 6α-triol	442.75
LZ19	Peroxyergosterol	428.72
LZ20	Ganoderal B	440.73
LZ21	Ganoderan B	454.76
LZ22	Ganoderic acid beta	500.74
LZ23	Ganoderic acid DM	468.74
LZ24	Ganodermic acid R	554.84
LZ25	Ganoderic acid Mi	528.85
LZ26	(E, 5S, 6S)-5-Acetoxy-6-[(3R, 5R, 10S, 13R, 14R, 17R)-3-hydroxy-4, 4, 10, 13, 14-pentamethyl-2, 3, 5, 6, 12, 15, 16, 17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylhept-2-enoic acid	512.80
LZ27	Ganoderic acid TQ	524.81
LZ28	Ganoderic acid TR	468.74
LZ29	Ganoderic acid Ⅴ	528.80
LZ30	Ganoderic acid Ⅴ1	512.75
LZ31	Ganoderic acid X	512.80
LZ32	Ganoderic acid Y	454.76
LZ33	Ganoderic acid Z	456.78
LZ34	Ganoderic aldehyde A	454.76
LZ35	Ganoderiol F	454.76
LZ36	Ganodermanondiol	456.78
LZ37	Ganodermatriol	456.78
LZ38	Ganodermenonol	438.76
LZ39	Ganodermic acid T-Q	512.80
LZ40	Ganodermic acid T-O	512.80
LZ41	Ganolucidic acid E	484.74
LZ42	Ganosporelactone B	530.72
LZ43	Lanosta-7, 9(11), 24-trien-15α-acetoxy-3α-hydroxy-23-oxo-26-oic acid	526.78
LZ44	Lanosta-7, 9(11), 24-trien-3α-acetoxy-15α-hydroxy-23-oxo-26-oic acid	526.78
LZ45	Lanosta-7, 9(11), 24-trien-3α-acetoxy-26-oic acid	496.80
LZ46	Lucialdehyde A	438.76
LZ47	Lucialdehyde B	452.74
LZ48	Lucialdehyde C	454.76
LZ49	Lucidenic acid A	458.65
LZ50	Lucidone A	402.58
LZ51	Lucidumol A	458.80
LZ52	Methyl ganoderic acid DM	482.77
LZ53	Methyl ganoderic acid TR	482.77
LZ54	Methyl lucidenate Q	474.70
LZ55	Cerevisterol	430.74
LZ56	Ergosta-7, 22E-dien-3β-ol	398.74
LZ57	Oleanic acid	456.70
Sedum sarmentosum Bunge
CP1	Liquiritigenin	256.27
CP2	Isorhamnetin	316.28
CP3	Sarmentosine	275.29
CP4	δ-Amyrone	424.70
CP5	Kaempferide	300.26
CP6	Sedumoside Ⅰ	388.50
CP7	Tricin	330.29
Polygoni Cuspidati Rhizoma et Radix
HZ1	6, 8-Dihydroxy-7-methoxyxanthone	258.24
HZ2	Physovenine	262.34
HZ3	Picralinal	366.45
HZ4	Physciondiglucoside	608.60
HZ5	Rhein	284.23
HZ6	Torachrysone-8-O-β-D-(6'-oxayl)-glucoside	480.46
HZ7	(+)-Catechin	290.29
HZ8	Resveratrol	228.26
HZ9	Polydatin	390.42
HZ10	Emodin	270.24
Multi-drug
A1	β-Sitosterol	414.79
A2	Luteolin	286.25
A3	Quercetin	302.25

No.	Uniprot	Gene	Target name	Degree
1	P19793	RXRA	Retinoic acid receptor RXR-alpha	32
2	P01375	TNF	Tumor necrosis factor	31
3	P49841	GSK3B	Glycogen synthase kinase-3 beta	22
4	P31749	AKT1	Serine/threonine-protein kinase 1	22
5	P45983	MAPK8	Mitogen-activated protein kinase 8	21
6	P05412	JUN	Transcription factor Jun	19
7	P42336	PIK3CA	Phosphatidylinositol 4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform	17
8	Q13133	NR1H3	Oxysterols receptor LXR-alpha	16
9	P45984	MAPK9	Mitogen-activated protein kinase 9	16
10	P05231	IL6	Interleukin-6	15
11	P10145	CXCL8	Interleukin-8	11
12	P01584	IL1B	Interleukin-1 beta	10
13	P37231	PPARG	Peroxisome proliferator-activated receptor gamma	8
14	Q07869	PPARA	Peroxisome proliferator-activated receptor alpha	8
15	P06213	INSR	Insulin receptor	7
16	P35568	IRS1	Insulin receptor substrate 1	6
17	P01583	IL1A	Interleukin-1 alpha	5
18	P36956	SREBF1	Sterol regulatory element-binding protein 1	5
19	Q96A54	ADIPOR1	Adiponectin receptor protein 1	5
20	Q86V24	ADIPOR2	Adiponectin receptor protein 2	5
21	P49327	FASN	Fatty acid synthase	4
22	P35638	DDIT3	DNA damage-inducible transcript 3 protein	3
23	P05198	EIF2S1	Eukaryotic translation initiation factor 2 subunit 1	2
24	Q96RI1	NR1H4	Bile acid receptor	2

No.	Uniprot	Gene	Target name	Degree
1	P19793	RXRA	Retinoic acid receptor RXR-alpha	32
2	P01375	TNF	Tumor necrosis factor	31
3	P49841	GSK3B	Glycogen synthase kinase-3 beta	22
4	P31749	AKT1	Serine/threonine-protein kinase 1	22
5	P45983	MAPK8	Mitogen-activated protein kinase 8	21
6	P05412	JUN	Transcription factor Jun	19
7	P42336	PIK3CA	Phosphatidylinositol 4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform	17
8	Q13133	NR1H3	Oxysterols receptor LXR-alpha	16
9	P45984	MAPK9	Mitogen-activated protein kinase 9	16
10	P05231	IL6	Interleukin-6	15
11	P10145	CXCL8	Interleukin-8	11
12	P01584	IL1B	Interleukin-1 beta	10
13	P37231	PPARG	Peroxisome proliferator-activated receptor gamma	8
14	Q07869	PPARA	Peroxisome proliferator-activated receptor alpha	8
15	P06213	INSR	Insulin receptor	7
16	P35568	IRS1	Insulin receptor substrate 1	6
17	P01583	IL1A	Interleukin-1 alpha	5
18	P36956	SREBF1	Sterol regulatory element-binding protein 1	5
19	Q96A54	ADIPOR1	Adiponectin receptor protein 1	5
20	Q86V24	ADIPOR2	Adiponectin receptor protein 2	5
21	P49327	FASN	Fatty acid synthase	4
22	P35638	DDIT3	DNA damage-inducible transcript 3 protein	3
23	P05198	EIF2S1	Eukaryotic translation initiation factor 2 subunit 1	2
24	Q96RI1	NR1H4	Bile acid receptor	2

Ingredient	-CDOCKER ENERGY/kcal·mol^-1
Co-crystallized ligand	34.474 6	18.688 0	30.333 0	29.126 0
Isorhamnetin	60.862 3	30.908 4	51.046 3	41.329 5
Salvianolic acid B	20.195 8	63.062 1	70.472 6	58.569 4
Emodin	39.100 8	32.491 2	52.176 7	37.718 6
Resveratrol	43.418 5	26.458 1	42.687 5	29.655 7
Rhein	45.940 7	26.458 1	48.422 7	32.405 8

Ingredient	-CDOCKER ENERGY/kcal·mol^-1
Co-crystallized ligand	34.474 6	18.688 0	30.333 0	29.126 0
Isorhamnetin	60.862 3	30.908 4	51.046 3	41.329 5
Salvianolic acid B	20.195 8	63.062 1	70.472 6	58.569 4
Emodin	39.100 8	32.491 2	52.176 7	37.718 6
Resveratrol	43.418 5	26.458 1	42.687 5	29.655 7
Rhein	45.940 7	26.458 1	48.422 7	32.405 8

Ingredient	MW/g·mol^-1	LogP	HBD	HBA	PSA/Å	Rotatable bond	Water solubility/log mol·L^-1	Caco-2 permeability/log P_app	Intestinal absorption/%	CYP2D6 inhibitor	Hepatotoxicity
Isorhamnetin	316.26	2.291	4	7	128.792	2	-3.000	-0.003	76.014	No	No
Salvianolic acid B	718.62	3.334	9	14	292.421	12	-2.892	-1.570	9.902	No	No
Emodin	270.24	1.887	3	5	113.283	0	-2.892	1.613	85.629	No	No
Resveratrol	228.24	2.973	3	3	98.911	2	-3.178	1.170	90.935	No	No
Rhein	284.22	1.571	3	5	117.445	1	-2.843	-0.241	55.000	No	No

Ingredient	MW/g·mol^-1	LogP	HBD	HBA	PSA/Å	Rotatable bond	Water solubility/log mol·L^-1	Caco-2 permeability/log P_app	Intestinal absorption/%	CYP2D6 inhibitor	Hepatotoxicity
Isorhamnetin	316.26	2.291	4	7	128.792	2	-3.000	-0.003	76.014	No	No
Salvianolic acid B	718.62	3.334	9	14	292.421	12	-2.892	-1.570	9.902	No	No
Emodin	270.24	1.887	3	5	113.283	0	-2.892	1.613	85.629	No	No
Resveratrol	228.24	2.973	3	3	98.911	2	-3.178	1.170	90.935	No	No
Rhein	284.22	1.571	3	5	117.445	1	-2.843	-0.241	55.000	No	No

基于网络药理学及计算机辅助药物设计研究护肝宁片治疗非酒精性脂肪性肝病的作用机制

PDF下载

陈聪 , 周香辉 , 张兵 , 彭彦芬 , 杨新平 , 余启明 ^* , 谭相端 ^*

药学学报 | 研究论文 2023,58(3): 695-710

收起

药学学报 | 研究论文 2023, 58(3): 695-710

基于网络药理学及计算机辅助药物设计研究护肝宁片治疗非酒精性脂肪性肝病的作用机制

全屏

陈聪, 周香辉, 张兵, 彭彦芬, 杨新平, 余启明^*, 谭相端^*

作者信息

桂林医学院药学院, 广西桂林 541199

通讯作者:

*余启明, Tel: 86-773-2303428, E-mail: qm_yu19@glmc.edu.cn;

谭相端, E-mail: tandy@glmc.edu.cn

Research of the mechanism of Huganning tablet in the treatment of nonalcoholic fatty liver disease based on network pharmacology and computer-aided drug design

Cong CHEN, Xiang-hui ZHOU, Bing ZHANG, Yan-fen PENG, Xin-ping YANG, Qi-ming YU^*, Xiang-duan TAN^*

Affiliations

College of Pharmacy, Guilin Medical University, Guilin 541199, China

出版时间: 2023-03-12 doi: 10.16438/j.0513-4870.2022-1046

文章导航

摘要

收起

基于网络药理学与计算机辅助药物设计探讨护肝宁片(Huganning tablet, HGNP) 治疗非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD) 的作用机制。通过TCMSP数据库、Swiss Target Prediction数据库、中国药典(2015版) 及文献检索确定HGNP的潜在活性成分及作用靶点, 并借助GeneCards数据库检索到的NAFLD疾病相关靶点进行交集整合, 获取HGNP治疗NAFLD的潜在作用靶点。运用R软件中bioconductor生物信息软件包对潜在作用靶点进行GO (gene ontology) 和KEGG (Kyoto encyclopedia of genes and genomes) 富集分析, 利用Cytoscape软件构建出“潜在活性成分-关键靶点-通路”网络, 整体探究潜在活性成分与关键靶点、通路、疾病间的关联。基于上述分析结果, 采用Discovery Studio 2020软件将HGNP中的潜在活性成分与网络图中度值排名靠前的关键靶点进行分子对接分析, 并进行分子动力学模拟、结合自由能计算、类药性分析和ADMET性质预测。体外实验使用HepG2细胞构建脂肪变性模型, 根据细胞油红O染色与甘油三酯(triglyceride, TG) 含量检测实验, 验证5个关键化合物对肝细胞脂肪变性的改善作用。筛选获得141个潜在活性成分和151个潜在作用靶点, 通过GO和KEGG富集分析, 分别得到2 526个条目和151条通路。分子对接结果显示, 异鼠李素(isorhamnetin)、丹酚酸B (salvianolic acid B)、大黄素(emodin)、白藜芦醇(resveratrol)、大黄酸(rhein) 5个成分与关键靶点[维甲酸受体RXR-α (retinoic acid receptor RXR-alpha, RXRA)、肿瘤坏死因子(tumor necrosis factor, TNF)、糖原合酶激酶(glycogen synthase kinase-3 beta, GSK3B)、丝氨酸/苏氨酸蛋白激酶1 (serine/threonine-protein kinase 1, AKT1)] 显示出较强的结合能力, 推测为HGNP治疗NAFLD的关键化合物。根据分子动力学模拟学模拟和结合自由能计算结果, 进一步验证了异鼠李素、丹酚酸B与关键靶点的结合具有较好的结构稳定性及结合亲和力。通过类药性分析与ADMET性质预测结果, 更全面地分析5个关键化合物的类药性、药代动力学性质及毒性。体外实验表明, 异鼠李素、丹酚酸B、大黄素、白藜芦醇、大黄酸均能改善HepG2细胞的脂肪变性情况, 证实了本研究的可靠性。综上, 本研究基于网络药理学、计算机辅助药物设计和体外实验验证, 在多层面上探讨了HGNP治疗NAFLD的作用机制, 为其临床应用提供依据。

关键词

护肝宁片 / 非酒精性脂肪性肝病 / 网络药理学 / 计算机辅助药物设计 / 作用机制

Abstract

收起

In this study, we explored the mechanism of Huganning tablet (HGNP) in the treatment of nonalcoholic fatty liver disease (NAFLD) based on network pharmacology and computer-aided drug design. Firstly, the potential ingredients and targets of HGNP were identified from TCMSP database, Swiss Target Prediction database, Chinese pharmacopoeia (2015) and literatures, and then the targets of HGNP intersected with NAFLD disease targets that obtained in GeneCards database to acquired potential targets. The bioconductor bioinformatics package of R software was used for gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. The network of "potential ingredient-key target-pathway" was formed in Cytoscape software to study the interactions between potential ingredients of HGNP, key targets, pathways and NAFLD. Based on the results of network pharmacology, the molecular docking analysis of the key targets and potential active ingredients in HGNP tablets with top degree in the network was conducted using Discovery Studio 2020 software, followed by molecular dynamics simulations, binding free energy calculation, drug-likeness properties analysis and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties prediction. In vitro, HepG2 cells were used to establish steatosis model, and the effects of five key compounds on hepatocyte steatosis were analyzed by oil red O staining and triglyceride (TG) content determination. The results showed that 141 ingredients and 151 potential targets were obtained. A total of 2 526 items and 151 pathways were identified by GO and KEGG enrichment analysis. The molecular docking suggested that five components, isorhamnetin, salvianolic acid B, emodin, resveratrol and rhein, exhibited strong binding ability with key targets [retinoic acid receptor RXR-alpha (RXRA), tumor necrosis factor (TNF), glycogen synthase kinase-3 beta (GSK3B), serine/threonine-protein kinase 1 (AKT1)]. It was further verified that isorhamnetin and salvianolic acid B bind to key targets with good structural stability and binding affinity based on molecular dynamics simulations and binding free energy calculations. The drug-likeness properties, pharmacokinetic properties and toxicity of five key compounds were more comprehensively analyzed through drug-likeness properties analysis and ADMET properties prediction. In vitro, all five compounds, isorhamnetin, salvianolic acid B, emodin, resveratrol, and rhein, improved hepatocyte steatosis of HepG2 cells, confirming the reliability of the present study. In conclusion, based on network pharmacology, computer-aided drug design and in vitro validation, this study investigated the mechanism of HGNP for the treatment of NAFLD at multiple levels and provided a basis for its clinical application.

Key words

Huganning tablet / nonalcoholic fatty liver disease / network pharmacology / computer-aided drug design / mechanism

引用本文

陈聪, 周香辉, 张兵, 彭彦芬, 杨新平, 余启明, 谭相端. 基于网络药理学及计算机辅助药物设计研究护肝宁片治疗非酒精性脂肪性肝病的作用机制. 药学学报, 2023 , 58 (3) : 695 -710 . DOI: 10.16438/j.0513-4870.2022-1046

Cong CHEN, Xiang-hui ZHOU, Bing ZHANG, Yan-fen PENG, Xin-ping YANG, Qi-ming YU, Xiang-duan TAN. Research of the mechanism of Huganning tablet in the treatment of nonalcoholic fatty liver disease based on network pharmacology and computer-aided drug design[J]. Acta Pharmaceutica Sinica, 2023 , 58 (3) : 695 -710 . DOI: 10.16438/j.0513-4870.2022-1046

正文

收起

非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD) 是指并非由长期大量饮酒和其他明确的损肝因素所引起的, 以肝细胞中脂质蓄积为病理改变的肝脏代谢性疾病^[1]。NAFLD患者由于肝脏代谢功能紊乱, 会导致大量脂质蓄积于肝细胞中(单纯性脂肪肝), 从而引起脂肪变性、肝细胞损伤、非酒精性脂肪性炎症、肝硬化、肝纤维化等一系列病理现象产生^[2]。随着人们生活水平的不断提高, NAFLD发病率逐年上升, 已成为全球最常见的慢性肝病, 在中国也已超过慢性乙型肝炎成为第一大慢性肝病^[3]。目前NAFLD的发病机制尚不完全清楚, 临床药物治疗如二甲双胍、吡格列酮等, 主要是针对NAFLD相关的代谢综合征、2型糖尿病、心血管疾病等方面, 而对患者并存的非酒精性脂肪性肝炎及肝纤维化均无肯定的治疗效果^[4]。因此, 研究治疗NAFLD的中药复方, 从调血脂、抗氧化、抗炎、抗纤维化、改善胰岛素抵抗等多方面改善NAFLD, 被认为是可行的治疗方案^[5]。

护肝宁片(Huganning tablet, HGNP) 由虎杖(Polygoni Cuspidati Rhizoma et Radix)、垂盆草(Sedum sarmentosum Bunge)、丹参(Salvia miltiorrhiza)、灵芝(Ganoderma lucidum) 4味中药组成, 其中虎杖清热解毒、利湿退黄、化痰散瘀, 垂盆草利湿退黄, 丹参活血祛瘀、理气止痛, 灵芝补益肝肾、益气养血, 四药合用可共奏清热利湿、保肝退黄、活血化瘀、理气止痛之功效, 是治疗各种急、慢性肝炎的常用中成药, 能显著改善急、慢性肝炎患者的肝功能和临床症状^[6]。近年研究发现, HGNP在治疗NAFLD方面亦有不错疗效, 可改善NAFLD患者的血脂、肝功能等生化指标及肝脏超声影像学, 且具有较好安全性^[7]。基础研究显示, HGNP能改善NAFLD模型大鼠肝组织的脂肪变性、氧化应激、炎症和纤维化, 但其治疗NAFLD的具体作用机制尚未研究清楚^[8]。网络药理学是从生物网络的整体角度阐释疾病机制和药物作用机制的新兴学科, 其研究理念契合传统中医药的整体论理念。运用网络药理学, 构建中药复方成分、靶点、通路、疾病间的整体作用网络, 可系统预测药物治疗疾病的作用机制^[9]。计算机辅助药物设计(computer-aided drug design, CADD) 是在合理药物设计探索中迅速发展起来的一种新药研究与开发技术, 其以计算机为工具, 充分利用已有的相关药物和靶标的知识, 通过理论计算、模拟和预测来指导和辅助人们在药物发现、药物作用机制等方面的研究^[10]。

本研究利用网络药理学方法, 对HGNP的化学成分、靶点进行数据挖掘, 构建出“潜在活性成分-关键靶点-通路”网络, 并结合计算机辅助药物分子设计与体外实验验证, 探究HGNP治疗NAFLD的作用机制, 为阐明HGNP的药效提供思路和方法。

材料与方法

收起

数据库与软件 TCMSP数据库(https://old.tcmsp-e.com/tcmsp.php), Swiss Target Prediction数据库(http://www.swisstargetprediction.ch/), CNKI数据(https://www.cnki.net/), PubMed数据库(https://pubmed.ncbi.nlm.nih.gov/), PubChem数据库(https://pubchem.ncbi.nlm.nih.gov/), PDB数据库(https://www.rcsb.org/), GeneCards数据库(https://www.genecards.org/), Venny 2.1在线软件作图工具平台(https://bioinfogp.cnb.csic.es/tools/venny/), pkCSM数据库(https://biosig.lab.uq.edu.au/pkcsm/), Cytoscape 3.9.0软件, R.4.1.2软件, Discovery Studio 2020软件, Gromacs软件和g_mmpbsa软件。

HGNP的潜在活性成分与靶点的获取 在TCMSP数据库中, 以HGNP的药材垂盆草、灵芝、丹参、虎杖为关键词进行检索, 对检索到的成分通过口服生物利用度(oral bioavailability, OB) ≥ 30%和类药性(drug-likeness, DL) ≥ 0.18为标准进行筛选, 得到其潜在活性成分。为避免HGNP中关键的活性成分被上述条件筛去, 通过查阅中国药典(2015版)、CNKI数据库与PubMed数据库中相关文献补充4味药材中的主要成分或具有明确药理活性的活性成分, 将补充成分整合到TCMSP数据库的筛选结果中。从TCMSP数据库中下载HGNP靶点信息, 并通过Swiss Target Prediction数据库对缺乏靶点信息的化合物进行靶点预测, 整合去重后获得HGNP靶点。

HGNP治疗NAFLD的潜在靶点的获取 采用GeneCards数据库, 物种设置为“homo sapiens”, 输入关键词“nonalcoholic fatty liver disease”进行检索, 整合去重后获得NAFLD相关靶点。在Venny 2.1在线软件作图工具平台上分别导入HGNP的药物靶点与NAFLD相关靶点, 绘制韦恩图, 两者的交集靶点即为HGNP治疗NAFLD的潜在靶点。

潜在靶点的GO富集分析和KEGG通路分析 为深入了解HGNP治疗NAFLD的潜在靶点的功能及在信号通路中的作用, 应用R.4.1.2软件中的bioconductor生物信息软件包对潜在靶点进行GO (gene ontology) 和KEGG (Kyoto encyclopedia of genes and genomes) 富集分析, 分析结果以P < 0.05作为筛选条件, 并通过微生信作图网站进行可视化处理。

“潜在活性成分-关键靶点-通路”网络的构建 为更直观地观察中药的潜在活性成分与关键靶点、通路间的关联, 将“潜在活性成分-关键靶点”、“关键靶点-通路”间的相互关系列于表格中, 然后将其导入Cytoscape软件中建立“潜在活性成分-关键靶点-通路”网络关系图。利用Network Analyzer功能对网络进行拓扑学分析, 根据关键靶点的度值(degree) 进行排序, 排名前4位的靶点将用于后续的分子对接验证。

分子对接 采用Discovery Studio 2020软件构建关键靶点的分子对接模型, 与HGNP的潜在活性成分进行分子对接, 验证研究的可靠性, 并筛选出与关键靶点结合较好的成分。从PDB数据库下载关键靶点的蛋白晶体结构, 为保证对接的精度, 优先选择分辨率小于3 Å并包含共晶配体的晶体复合物。使用Discovery Studio 2020中Prepare Protein工具对蛋白进行除水、加氢等预处理。从PubChem数据库中下载HGNP潜在活性成分的结构, 导入Discovery Studio 2020后通过Prepare Ligand工具对潜在活性成分的进行结构优化。随后, 将关键靶点与潜在活性成分通过CDOCKER进行分子对接, 采用打分函数-CDOCKER ENERGY对分子对接的结果进行评价。

分子动力学模拟 使用Gromacs软件进行分子动力学模拟研究, 进一步分析关键化合物与关键靶点间的结合稳定性及结合亲和力。采用GROMOS96立场产生蛋白质-配体复合物的拓扑文件。将复合物放入周期性边界为1 nm的立方体盒子中, 将TIP3P水模型作为溶剂, 并通过添加Na⁺和Cl^-离子使得模拟体系中电荷达到平衡。在进行分子动力学模拟前, 首先对复合物进行能量最小化, 使其温度从0到300 K渐进加热, 然后再进行2个阶段的平衡: 100 ps的恒温恒容平衡和100 ps的恒温恒压平衡。平衡后体系的密度达到最优状态, 进行时长为10 ns的分子动力学模拟。

结合自由能的计算 本研究采用分子力学-泊松玻尔兹曼表面积法(molecular mechanics Poisson-Boltzmann surface area, MM/PBSA), 计算蛋白质-配体复合物的结合自由能。将分子动力学模拟的结果文件导入g_mmpbsa程序中, 通过MM/PBSA法计算复合物的结合自由能, 并进行能量分解, 分析各个氨基酸的结合自由能贡献值。结合自由能的计算如公式(1):

(1)$\Delta G_{\text {bind }}=G_{\text {complex }}-\left(G_{\text {receptor }}+G_{\text {ligand }}\right)$

其中, G_complex代表蛋白-配体复合物的结合能, G_receptor和G_ligand分别代表蛋白和配体在溶剂中的结合能。

类药性分析和ADMET性质预测 使用pkCSM数据库预测关键化合物的类药性及ADMET性质。在PubChem数据库下载关键化合物的结构文件, 并将其结构文件导入pkCSM数据库中。根据化合物的结构预测类药性和ADMET性质, 如分子质量(molecular weight, MW)、脂水分配系数(AlogP)、氢键受体(hydrogen bond acceptor, HBA) 和氢键供体(hydrogen bond donor, HBD) 的数量、可旋转键(rotatable bond) 数量和极性表面积(polar surface area, PSA)、水溶性(water solubility)、Caco-2细胞膜穿透性(Caco-2 permeability)、肠道吸收(intestinal absorption)、CYP2D6酶的抑制作用(CYP2D6 inhibitor) 及肝毒性(hepatoxicity)。

细胞与试剂 人肝癌细胞系HepG2细胞、人正常肝细胞系L02细胞(武汉普诺赛生命科技有限公司); 高糖DMEM培养基、1640培养基(美国Gibco公司); 青-链霉素、噻唑蓝(MTT)、油红O染色液(细胞专用) (北京索莱宝公司); 0.25%胰蛋白酶(上海碧云天生物技术有限公司); 胎牛血清(FBS, 杭州四季青公司); 丹酚酸B (salvianolic acid B)、大黄素(emodin)、大黄酸(rhein)、白藜芦醇(resveratrol)、异鼠李素(isorhamnetin)、牛血清白蛋白(BSA)、油酸、棕榈酸(上海阿拉丁生化科技股份有限公司); 甘油三酯(triglyceride, TG) 试剂盒(南京建成有限公司); BCA蛋白定量试剂盒(上海碧云天生物技术有限公司); 游离脂肪酸(FFA) 用油酸与棕榈酸2∶1配制而成; 异丙醇(国药集团化学试剂有限公司)。

主要仪器 二氧化碳培养箱(德国艾本德公司); 多功能酶标仪(美国赛默飞公司); DMi8倒置显微镜(德国徕卡公司)。

细胞培养 HepG2细胞培养于含10% FBS、1%青-链霉素的高糖DMEM培养基中, L02细胞培养于含10% FBS、1%青-链霉素的1640培养基中。细胞都于37 ℃、5% CO₂、饱和湿度的恒温培养箱中孵育。当细胞密度达到80%~90%时, 使用0.25%胰蛋白酶消化, 按比例1∶2传代。

细胞活力检测 取对数生长期的HepG2、L02细胞均匀接种于96孔板中, 待细胞贴壁后, 分别给予浓度为0、10、20、40、80、100、200 µmol·L^-1的药物于细胞培养箱中培养24 h。然后每孔加入20 µL MTT溶液反应, 避光孵育4 h。结束孵育后吸出孔内培养液, 每孔加入150 µL DMSO, 低速震荡, 使结晶充分溶解。在570 nm处测量各孔吸光度值。

细胞脂肪变性模型的构建 HepG2细胞是人肝癌细胞, 保留了正常肝细胞的糖脂代谢等绝大多数生理功能, 且具有体外培养简易、可更好耐受脂毒性等优点, 常用于研究肝细胞脂肪变性^[11]。取对数生长期HepG2细胞均匀接种于6孔培养板, 待细胞于孔中达到85%密度后, 将细胞分为对照组、模型组与给药组。对照组细胞用高糖DMEM培养基培养; 模型组细胞用0.5 mmol·L^-1 FFA培养; 给药组细胞在建模后加入药物处理24 h。

油红O染色 根据油红O染色试剂盒说明书, 将油红O染色A液与油红O染色B液按3∶2比例混合, 静置10 min, 过滤后得油红O染色工作液。吸出板内细胞培养基, 用PBS洗2次, 加4%多聚甲醛固定30 min。60%异丙醇浸洗1 min后, 加入新配制的油红O染色工作液染色20 min。以60%异丙醇漂洗30 s至间质清晰。再用苏木素染色液, 复染核2 min, 蒸馏水洗涤干净后在徕卡DMi8倒置显微镜下观察。

细胞TG含量检测 采用TG含量检测试剂盒, 通过GPO-PAP法测定细胞中TG含量。吸出孔中培养基, PBS洗2次, 胰蛋白酶消化2 min, 1 000 r·min^-1离心10 min, 弃上清液, 加入裂解液1% Triton X-100裂解细胞30 min, 充分裂解后, 根据TG试剂盒说明书, 将工作液A与工作液B按2∶1混合, 取2.5 µL上清液与250 µL混合好的工作液, 在37 ℃孵育10 min, 于510 nm检测吸光度值。

统计学分析 应用GraphPad Prism 8软件进行数据统计, 结果以均数±标准误(mean ± SEM) 表示, 采用单因素方差分析(one-way ANOVA) 方法进行统计学分析, P < 0.05认为差异有统计学意义。

结果

收起

1 HGNP潜在活性成分与靶点的获取

从TCMSP数据库检索HGNP成分, 根据OB ≥ 30%、DL ≥ 0.18为标准进行筛选后结合中国药典(2015版) 与相关文献补充重要化合物, 最终得出141个潜在活性成分, 包括垂盆草10个化学成分、虎杖13个化学成分、灵芝58个化学成分、丹参65个化学成分。其中木犀草素为垂盆草、虎杖、丹参的共有成分, 槲皮素为垂盆草、虎杖的共有成分, β-谷甾醇为垂盆草、虎杖、灵芝的共有成分。HGNP的潜在活性化合物信息见表 1。从TCMSP数据库中检索HGNP的靶点信息, 并通过Swiss Target Prediction数据库对缺乏靶点信息的化合物进行靶点预测, 根据Probability值对预测结果进行排序后取排名前10的靶点, 整合去重后获得433个药物靶点。

2 HGNP治疗NAFLD的潜在靶点的获取

以“nonalcoholic fatty liver disease”为关键词在GeneCards数据库中进行检索, 得到疾病靶点1 131个。将疾病靶点与HGNP的药物靶点分别导入Venny 2.1在线软件作图工具平台, 绘制韦恩图, 得到151个HGNP治疗NAFLD的潜在靶点(图 1)。

3 潜在靶点的GO富集分析和KEGG通路分析

通过R软件中“cluster profiler v4.2.2”生物信息包对151个潜在靶点进行GO富集分析与KEGG通路分析, 得到GO条目共2 526条(P < 0.05), 其中包括生物过程(biological process, BP) 条目2 331条、细胞组成(cell composition, CC) 条目51条、分子功能(molecular function, MF) 条目144个。根据P值对条目排序, 将各类别前10名富集结果进行可视化分析(图 2)。GO富集结果显示, BP方面主要涉及对营养水平的反应(response to nutrient level)、细胞对化学应激的反应(cellular response to chemical stress)、活性氧代谢过程(response to reactive oxygen species) 等生物过程。CC方面主要包括膜筏(membrane raft)、膜微区(membrane microdomain)、囊泡腔(vesicle lumen) 等细胞成分。MF方面主要涉及核受体的激动活性(nuclear receptor activity)、配体激活的转录因子的激动活性(ligand-activated transcription factor activity)、DNA结合转录因子的结合(DNA-binding transcription factor binding) 等分子功能。

KEGG通路富集分析得到P < 0.05的通路共152个, 根据P值进行排序, 排名前20的通路见图 3。通路富集结果主要涉及AGE-RAGE在糖尿病并发症中的信号通路(AGE-RAGE signaling pathway in diabetic complications)、脂肪和动脉粥样硬化通路(lipid and atherosclerosis)、胰岛素抵抗通路(insulin resistance)、丙型肝炎疾病通路(hepatitis C)、内分泌抵抗通路(endocrine resistance)、NAFLD等。值得注意的是, KEGG通路富集分析结果中, HGNP的24个潜在活性靶点富集于NAFLD疾病通路(表 2), 表明这些靶点与HGNP治疗NAFLD有较为关键的联系, 本研究将这些靶点作为关键靶点, 用于进一步的分析验证。

4 “潜在活性成分-关键靶点-通路”网络的构建

根据KEGG通路分析结果, 并结合中药潜在活性成分、关键靶点的信息, 利用Cytoscape软件构建“潜在活性成分-关键靶点-通路”网络, 如图 4所示, 包括187个节点、453条边。为筛选出关键靶点中作用较大的靶点, 利用Analyze Network功能对网络进行拓扑学分析, 根据度值进行排序。排名前4的靶点分别为维甲酸受体RXR-α (retinoic acid receptor RXR-alpha, RXRA)、肿瘤坏死因子(tumor necrosis factor, TNF)、糖原合酶激酶(glycogen synthase kinase-3 beta, GSK3B)、丝氨酸/苏氨酸蛋白激酶1 (serine/threonine-protein kinase 1, AKT1)。

5 分子对接验证

为了验证本网络药理学研究的准确性及筛选出HGNP潜在活性成分中治疗NAFLD的关键成分, 采用软件Discovery Studio 2020对4个关键靶点RXRA、TNF、GSK3B、AKT1分别建立分子对接模型, 把共晶配体提取出后重新对接到蛋白的活性位点中, 计算对接后的配体与共晶配体的均方根偏差(root-mean-square-deviation, RMSD) 值。结果显示, RXRA、TNF、GSK3B、AKT1分子对接模型的RMSD值分别为0.573 3、1.417 7、1.326 5、0.930 6 Å, 均小于2 Å, 表示4个分子对接模型具有较高的可靠性。将HGNP的141个潜在活性成分与上述4个对接模型进行分子对接研究, 对接结果以-CDOCKER ENERGY值进行排序, -CDOCKER ENERGY值越大, 说明成分与靶点的相互结合作用越强, 尤其是当成分与靶点分子对接的-CDOCKER ENERGY值大于共晶配体时, 可认为成分与靶点具有很强的结合作用。分子对接-CDOCKER ENERGY值排名前5的化合物如表 3所示, 异鼠李素、大黄素、白藜芦醇、大黄酸与4个关键靶点分子对接的-CDOCKER ENERGY值均大于共晶配体, 而丹酚酸B与靶点TNF、GSK3B、AKT1的分子对接中显示出最大的-CDOCKER ENERGY值。进一步分析潜在活性成分与关键靶点的结合模式, 以在分子对接中有较好结合活性的异鼠李素、丹酚酸B为例, 其中异鼠李素主要通过氢键、疏水键如π-π堆积作用力等与关键靶点结合(图 5), 而丹酚酸B主要通过离子键、氢键、疏水键与关键靶点结合(图 6)。根据上述分子对接结果, 筛选出异鼠李素、丹酚酸B、大黄素、白藜芦醇、大黄酸与关键靶点RXRA、TNF、GSK3B、AKT1有较好的结合活性, 推测为护肝宁片治疗NAFLD的关键化合物, 进行下一步的实验验证。

6 分子动力学模拟

分子动力学模拟作为研究生物大分子及其相互作用的有力工具, 已被广泛用于创新药物研究^[12]。本实验将在分子对接中表现良好的异鼠李素-RXRA, 丹酚酸B-GSK3B复合物进行分子动力学模拟。根据模拟结果计算复合物的RMSD和均方根波动(root mean square fluctuation, RMSF) 值, 评估整个复合物结构及各个氨基酸在动力学过程中的稳定程度。RMSD将初始构象作为参考对象, 通常用来检测分子动力学模拟过程中复合物结构的稳定性^[13]。由图 7A、B所示, 异鼠李素-RXRA和丹酚酸B-GSK3B复合物分别在模拟6和4 ns后趋于平衡, RMSD值稳定在0.25和0.3 nm, 表明两个复合物的骨架在模拟过程偏移程度较小, 复合物结构可以保持较好的稳定性。RMSF是衡量蛋白质中每个氨基酸残基在动力学模拟时间段内的波动情况的分析方法^[14]。较高的RMSF值代表该氨基酸残基具有较大的波动性; 相反地, 较小的RMSF值代表该氨基酸残基的波动性小。根据图 7C、D所示, 异鼠李素-RXRA复合物模拟过程中大部分氨基酸残基RMSF为0.1~0.3 nm; 而复合物丹酚酸B-GSK3B模拟过程中大部分氨基酸残基RMSF值为0.1~0.4 nm。结合RMSD与RMSF分析, 表明2个化合物与相应蛋白质的结合体系具有较好的稳定性。

7 结合自由能的计算

计算化合物与靶点的结合自由能, 通常用来更精确地探究配体小分子与受体之间的结合强度和亲和力^[15]。化合物与靶点结合所需的结合自由能越少, 表示结合所需的能量越低, 越有利于化合物与靶点的结合^[16]。本实验通过MM/PBSA法计算异鼠李素-RXRA和丹酚酸B-GSK3B两个复合物中相应的化合物与蛋白质结合时所需的结合自由能, 并对结合自由能进行能量分解, 分析各个氨基酸的结合自由能贡献值。结果显示, 异鼠李素-RXRA和丹酚酸B-GSK3B两个复合物的结合自由能分别为-164.093、-120.597 kJ·mol^-1, 进一步验证了异鼠李素、丹酚酸B与关键靶点的结合能力。另外, 根据图 8所示, 异鼠李素-RXRA复合物中, 氨基酸残基PHE313、ILE268、LEU309对结合自由能有较大的贡献值, 分别为-12.395、-9.101、-7.016 kJ·mol^-1; 而在丹酚酸B-GSK3B复合物中, 氨基酸残基ARG141、ILE62、PRO136对结合自由能贡献值最大, 分别为-59.565、-24.248、-22.181 kJ·mol^-1。

8 类药性分析与ADMET性质预测

研究表明^[17], 口服吸收有效的化合物对于Lipinski五规则的符合率达到90%, 而Veber规则可更好地阐释口服生物利用度与化合物结构的关系。因此, 本研究基于Lipinski五规则和Veber规则(MW ≤ 500 g·mol^-1, LogP ≤ 5, HBA ≤ 10, HBD ≤ 5, PSA ≤ 140 Å, rotatable bonds ≤ 10), 更全面地分析护肝宁片中关键化合物的类药性。结果如表 4所示, 关键化合物异鼠李素、大黄素、白藜芦醇、大黄酸的理化性质均符合Lipinski五规则和Veber规则。而丹酚酸B除了LogP满足类药性规则外, 其余性质不符合Lipinski五规则和Veber规则。

药物的ADMET性质, 即药物在体内的吸收(absorption)、分布(distribution)、代谢(metabolism)、排泄(excretion) 及毒性(toxicity), 是影响药物疗效的关键因素^[18]。ADMET预测结果显示(表 4), 大黄素、白藜芦醇显示出较高的体外Caco-2细胞膜透过率(> 0.9 log P_app); 异鼠李素、大黄素、白藜芦醇、大黄酸的肠道吸收率高于低肠道吸收分子的阈值30%, 其中大黄素、白藜芦醇的肠道吸收率达到85.629%、90.935%, 显示出较好的肠道吸收; 5个关键化合物均预测出对CYP2D6代谢酶无抑制作用, 且无肝毒性。

9 细胞活力检测

根据MTT法检测关键化合物对HepG2、L02细胞活力的影响, 并筛选合适的给药浓度。由图 9所示, 5个关键化合物在浓度≤ 40 µmol·L^-1时对HepG2和L02细胞的细胞活力影响较低。随着白藜芦醇、大黄酸的给药浓度大于80 µmol·L^-1, HepG2、L02细胞的细胞活力显著下降; 异鼠李素、丹酚酸B浓度200 µmol·L^-1时仍未降低L02细胞的细胞活力, 而对HepG2细胞产生明显细胞抑制作用。因此, 为避免细胞活力受到影响, 选定40 µmol·L^-1为合适的浓度用于后续给药处理。

10 细胞油红O染色与TG含量检测

肝细胞内TG的异常蓄积会引起脂肪变性, 是NAFLD发病的重要诱因之一^[19]。采用油红O染色与细胞TG含量检测实验验证HGNP中的关键化合物对肝细胞脂肪变性的改善作用。如图 10、11所示, 与对照组相比, 0.5 mmol·L^-1 FFA诱导24 h后的模型组细胞内红色脂滴大量生成, TG含量显著提升, 表明成功构建细胞脂肪变性模型; 而后分别经过40 µmol·L^-1异鼠李素、丹酚酸B、大黄素、白藜芦醇、大黄酸处理24 h, 5个给药组细胞内的红色油脂与TG含量在不同程度上减少, 细胞脂肪变性情况均有所改善。其中异鼠李素、大黄素对FFA诱导的细胞脂肪变性模型的改善作用更为明显。以上实验结果验证了上述5个化合物可能为HGNP治疗NAFLD的重要活性成分, 且进一步证明了本研究网络药理学与计算机辅助药物设计部分的可靠性。

讨论

收起

随着人们饮食习惯与生活节奏的变化, NAFLD发病率增长迅速且呈低龄化趋势, 对人类生命健康产生严重危害^[20]。NAFLD的发病机制至今还未明确, 最为大家广泛接受的是“二次打击”假说, 其中“初次打击”为患者因胰岛素抵抗、肥胖等因素导致肝细胞发生脂肪变性, 肝脏的耐受能力下降。“二次打击”则是在初次打击基础上, 由氧化应激、炎性细胞因子等共同作用导致肝细胞发生炎症、坏死或纤维化^{[21, 22]}。目前临床尚无特异性药物治疗NAFLD, 多是在改变患者生活方式的基础上(调整饮食结构、运动), 使用药物如胰岛素增敏剂、降血脂药、抗氧化剂等进行治疗^{[23, 24]}。西药因其成分和靶点较为单一, 对于NAFLD这种复杂的代谢性疾病, 往往只能改善部分指标, 且易产生不良反应^[25]。而中药复方具有多成分、多途径、多靶点协同作用的特点, 可从多方面改善NAFLD^[26-28]。

HGNP由虎杖、垂盆草、灵芝、丹参4味中药组成^[29]。现代医学认为, 方中的虎杖具有抗炎、改善胰岛素抵抗、抗氧化应激、调节脂质代谢、肝保护等作用^[30]; 丹参可发挥调节肝内脂质代谢、降低抗氧自由基、改善肝脏微循环, 减轻肝纤维化等作用^{[31, 32]}; 垂盆草可降低血清谷丙转氨酶(ALT) 水平, 保护肝细胞, 减轻肝细胞损伤^[33]; 而灵芝可降低血清TG、总胆固醇及低密度脂蛋白含量, 对抗氧化应激, 促进肝细胞再生^[34]。近年来研究表明, HGNP在治疗NAFLD方面具有不错的疗效, NAFLD患者的血脂、肝功能、肝纤维化等指标相较于治疗前明显改善^[7], 但因其作用机制方面并未研究透彻, 阻碍了其在治疗NAFLD方面进一步的临床应用。

本研究通过网络药理学方法, 并结合计算机辅助药物分子设计技术与体外实验验证, 研究HGNP治疗NAFLD的作用机制。在GO富集分析、KEGG通路分析结果中, 通路主要富集于AGE-RAGE在糖尿病并发症中的信号通路、脂肪和动脉粥样硬化通路、胰岛素抵抗通路、内分泌抵抗通路、非酒精性脂肪性肝病通路、脂肪细胞因子信号通路、IL-17信号通路、FoxO信号通路、AMPK信号通路等。NF-κB是重要的基因转录调节因子, 参与调控多种炎症基因、黏附分子和蛋白酶基因的表达, 在肝脏炎症、氧化应激、纤维化等过程中发挥重要作用, 而AGE-RAGE信号通路可通过调控NF-κB, 与NAFLD在多方面密切联系^{[35, 36]}。FoxO是一类转录因子, 广泛作用于脂肪细胞、肝细胞、心肌细胞等多种细胞, 参与胰岛素合成及胰岛素对肝细胞糖脂代谢的调节等过程^[37]。Matsumoto等^[38]发现, 肝脏中的FoxO过度表达会引起TG合成上升、降低游离脂肪酸的氧化, 从而促进肝脏脂肪变性。AMPK被称为“细胞能量平衡感受器”, 是体内不可缺少的蛋白激酶, 参与多种代谢过程, 是细胞内调节糖、脂代谢的关键分子^[39]。根据以上推断, HGNP可能通过作用于缓解胰岛素抵抗、调节脂质和糖代谢、调节炎症反应、调节氧化应激等的相关靶点、通路, 产生治疗NAFLD的效果。

根据“潜在活性成分-关键靶点-通路”网络, 发现HGNP的潜在活性成分、关键靶点、通路、疾病间存在多种关联, 其中网络中连接度值较高的靶点为RXRA、TNF、GSK3B、AKT1, 可能是其治疗NAFLD较为关键的靶点。RXRA作为类固醇-甲状腺激素受体超家族的一员, 可与视黄酸受体(RARs) 形成同二聚体或异二聚体, 从而调节细胞的增殖、分化、脂质代谢等过程^[40]。另外, RXRA也可与许多核受体如PPARA、LXR、RARB等形成二聚体, 参与核受体对靶基因的调控过程^[41]。其中, 异二聚体RXRA/PPARA的形成对于PPARA调节脂肪酸氧化基因的转录活性发挥关键作用^[42]。TNF是肿瘤坏死因子, 在炎症反应、细胞免疫、肿瘤免疫等多种生理、病理过程中发挥关键作用^[43]。研究发现, NAFLD模型小鼠中结肠组织的TNF表达水平相比于正常小鼠明显升高, 而HGNP可降低TNF在NAFLD小鼠结肠组织中的表达^[7]。GSK3B是一种特殊的多功能丝氨酸/苏氨酸激酶, 能磷酸化糖原合成酶并使其失活, 参与新陈代谢、基因表达和器官发育等生理过程^[44]。有研究表明, 抑制靶点GSK3B的表达可刺激葡萄糖的吸收, 促进糖原合成, 并缓解胰岛素抵抗^[45]。AKT1是一种丝氨酸/苏氨酸蛋白激酶, 可作为磷酸肌醇3激酶(PI3K)/AKT信号通路的关键调节因子, 介导细胞生长、增殖、细胞周期调节等过程^{[46, 47]}。

基于上述网络药理学研究, 对HGNP治疗NAFLD的潜在活性成分、作用靶点、作用通路进行了初步探讨, 但仍缺乏更深入的分析与验证。分子对接、分子动力学模拟、结合自由能计算等计算机辅助药物设计技术, 可帮助人们从分子水平上对中药的潜在活性成分进行研究, 进一步寻找并阐释中药中的潜在活性成分与机体靶点受体间的相互作用情况, 为中药的现代化挖掘及发现潜在活性成分提供可靠支撑^{[48, 49]}。本研究发现, 异鼠李素、丹酚酸B、大黄素、白藜芦醇、大黄酸与关键靶点RXRA、TNF、GSK3B、AKT1有较好结合能力, 预测为HGNP治疗NAFLD的关键化合物, 分子动力学模拟分析也验证了异鼠李素、丹酚酸B与关键靶点间的结合稳定性。结合自由能由于其更全面地分析化合物与靶点的相互作用力, 通常相较于分子对接可更精确地分析化合物与靶点的结合能力^{[50, 51]}。本文根据结合自由能的计算进一步验证了异鼠李素、丹酚酸B与相应关键靶点的结合能力, 并分析化合物与靶点中氨基酸残基的相互作用情况。根据类药性分析, 异鼠李素、大黄素、白藜芦醇、大黄酸的理化性质满足类药性规则, 表明其口服吸收有效, 具有较好的口服生物利用度。ADMET性质预测结果显示, 大黄素、白藜芦醇拥有较好的细胞膜透过性与肠道吸收。异鼠李素、丹酚酸B、大黄素、白藜芦醇、大黄酸对CYP2D6代谢酶没有抑制作用, 且无肝毒性。

为验证HGNP中关键化合物对NAFLD的治疗作用, 使用FFA在体外诱导构建肝细胞的脂肪变性模型, 发现异鼠李素、丹酚酸B、大黄素、白藜芦醇、大黄酸可使细胞内的脂滴及TG含量在不同程度上减少, 对脂肪变性产生一定的积极作用。其中, 异鼠李素、大黄素改善脂肪变性的效果最为明显。

综上所述, 本研究首先通过网络药理学分析, 对HGNP治疗NAFLD的潜在靶点进行GO与KEGG富集分析, 并构建“潜在活性成分-关键靶点-通路”网络, 初步探讨了HGNP可通过多成分、多靶点、多通路治疗NFALD的作用机制。根据计算机辅助药物设计进一步研究HGNP治疗NAFLD的药效物质基础及分子作用机制, 并推测获得5个关键成分异鼠李素、丹酚酸B、大黄素、白藜芦醇、大黄酸。体外实验验证了5个关键成分具有改善肝细胞脂肪变性作用。本研究结合网络药理学、计算机辅助药物设计、体外实验, 探讨了HGNP治疗NAFLD的作用机制, 为护肝宁片的临床应用和机制研究提供参考。

作者贡献: 谭相端和余启明提出整体研究思路, 以及负责论文撰写的指导与修改; 陈聪负责网络药理学、部分体外活性测试和分子动力学模拟, 以及文章撰写; 周香辉负责计算机辅助药物设计部分; 张兵负责部分体外活性测试; 彭彦芬和杨新平负责相关文献的调研与收集。

利益冲突: 所有作者均声明没有利益冲突。

基金

收起

国家自然科学基金资助项目(82060627)
广西自然科学基金项目(2020GXNSFAA159149)
广西研究生教育创新计划项目(YCSW2022367)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

Zhao HD, Yang F, Zhan L. Research advances in pathogenesis of non-alcoholic fatty liver disease[J]. Acad J Chin PLA Med Sch (解放军医学院报), 2022, 43: 366-370.

[2]

Ekstedt M, Nasr P, Kechagias S. Natural history of NAFLD/NASH[J]. Curr Hepatol Rep, 2017, 16: 391-397.

https://doi.org/10.1007/s11901-017-0378-2

[3]

Ni R, Li CX, Ju J. Recent advance in the treatment of non-alcoholic fatty liver disease[J]. Chin J Gastroenterol Hepatol (胃肠病学和肝病学杂志), 2022, 31: 136-140.

[4]

Ke SJ, Yang HY, Liu LX. Research progress of pathogenesis and treatment in non-alcoholic liver disease[J]. Med Recapit (医学综述), 2020, 26: 3146-3150.

[5]

Guo L. Research progress of the mechanism and therapy of non-alcoholic fatty liver disease[J]. Chin Bull Life Sci (生命科学), 2018, 30: 1166-1172.

[6]

Huang W, Gao SQ, Zhang BH. Clinical application of the efficacy and safety of proheparinum tablet[J]. Eval Anal Drug Use Hosp China (中国医院用药评价与分析), 2010, 10: 751-753.

[7]

Wang ZJ, Liu XY, Wang XL. Effects of Huganning tablets on liver function, serum lipid parameters and iconography in patients with non-alcoholic fatty liver disease[J]. Hebei J Tradit Chin Med (河北中医), 2016, 38: 353-355.

[8]

Zhao YT, Shu XB, Yang ZX, et al. Effects of Huganning tablets on intestinal mucosal mechanical barrier in mice with non-alcoholic fatty liver disease[J]. J Shanghai Univ Tradit Chin Med (上海中医药大学学报), 2021, 35: 58-65.

[9]

Liu ZH, Sun XB. Network pharmacology: new opportunity for the modernization of traditional Chinese medicine[J]. Acta Pharm Sin (药学学报), 2012, 47: 696-703. http://www.yxxb.com.cn/aps/cn/article/id/f4cd642f-da9e-4f29-9a49-8680b02d04d2

[10]

Macalino SJY, Gosu V, Hong S, et al. Role of computer-aided drug design in modern drug discovery[J]. Arch Pharm Res, 2015, 38: 1686-1701.

https://doi.org/10.1007/s12272-015-0640-5

[11]

Luo Y, He XP, Li X, et al. Establishment and comparative analysis of several kinds of cell fatty degeneration model[J]. Chin Arc Tradit Chin Med (中华中医药学刊), 2017, 35: 2074-2077.

[12]

Zhao H, Caflisch A. Molecular dynamics in drug design[J]. Eur J Med Chem, 2015, 91: 4-14.

https://doi.org/10.1016/j.ejmech.2014.08.004

[13]

Zhang YH, Zhang RS, Hu RJ, et al. Successful molecular dynamics and binding energy calculation of HIV-1 Tat complexed with P-TEFb[J]. J Lanzhou Univ (Nat Sci) (兰州大学学报(自然科学版)), 2011, 47: 114-121.

[14]

Zhang H, Lv JH, Mu JB, et al. Molecular dynamics simulation and antibacterial mechanism of 3MBA derivatives as FtsZ protein inhibitors[J]. Acta Phys Chim Sin (物理化学学报), 2015, 31: 566-575.

https://doi.org/10.3866/PKU.WHXB201501061

[15]

Hu RJ. Molecular Modeling Studies of HIV-1 Reverse Transcription and Some of Its Inhibitors (HIV-1逆转录酶及其抑制剂的分子模拟研究) [D]. Lanzhou: Lanzhou University, 2009.

[16]

Li CH, Zhang M, Lin J, et al. Analysis of in vitro activity and compatibility of Dunhuang Yifang Dabupi Decoction on gastric cancer based on computer-aided drug design[J]. Acta Pharm Sin (药学学报), 2022, 57: 2087-2100. http://www.yxxb.com.cn/aps/cn/article/doi/10.16438/j.0513-4870.2022-0005

[17]

Walters WP. Going further than Lipinski's rule in drug design[J]. Expert Opin Drug Discov, 2012, 7: 99-107.

https://doi.org/10.1517/17460441.2012.648612

[18]

Hu BC, Tian JX, Zhang YT, et al. Online prediction of compound's druggability[J]. Chin J Med Chem (中国药物化学杂志), 2022, 32: 90-101.

[19]

Zhao LP, Cheng YY, Fan TY, et al. Synthesis and evaluation on triglyceride inhibitory activities of novel indole alkaloids[J]. Acta Pharm Sin (药学学报), 2022, 57: 433-440. http://www.yxxb.com.cn/aps/cn/article/doi/10.16438/j.0513-4870.2021-1439

[20]

Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact[J]. J Hepatol, 2018, 68: 268-279.

https://doi.org/10.1016/j.jhep.2017.09.003

[21]

Dong S, Liu P, Sun MY. Role of "two-hit" in non-alcoholic fatty liver disease[J]. J Clin Hepatol (临床肝胆病杂志), 2012, 28: 551-555.

[22]

Byrne CD, Targher G. NAFLD: a multisystem disease[J]. J Hepatol, 2015, 62: 47-64.

https://doi.org/10.1002/hep.27771

[23]

Dong S, Liu P, Sun MY. The development of treatment for NAFLD[J]. Liaoning J Tradit Chin Med (辽宁中医杂志), 2013, 40: 599-602.

[24]

Maurice J, Manousou P. Non-alcoholic fatty liver disease[J]. Clin Med, 2018, 18: 245-250.

[25]

Qian K, Liu YY, Zhang Y, et al. Research progress on molecular mechanism of traditional Chinese medicine against non-alcoholic fatty liver disease[J]. Chin Tradit Herb Drugs (中草药), 2020, 51: 5083-5092.

[26]

Hu YY. Advantages and prospects of traditional Chinese medicine in treating nonalcoholic fatty liver disease[J]. World Chin Med (世界中医药), 2015, 10: 149-152.

[27]

Xu Y, Tao Y, Gou XJ. Differentiation and analysis on TCM etiology and pathogenesis of non-alcoholic fatty liver[J]. Chin Arch Tradit Chin Med (中华中医药学刊), 2016, 34: 2586-2589.

[28]

Wang YL, Zhang HX, Li WL, et al. Analysis and thinking on TCM preventing and treating NAFLD[J]. Inf Tradit Chin Med (中医药信息), 2022, 38: 85-89.

[29]

Xu H, Zheng SM, Jiang MD, et al. Therapeutic effects of Huganning pill on patients with drug induced hepatitis[J]. Chin J Integr Tradit West Med Dig (中国中西医结合消化杂志), 2009, 17: 34-36.

[30]

Li SD, Chen XJ, Liu JK, et al. Signaling pathways involved in the active components of Polygonum cuspidatum in treatment of nonalcoholic fatty liver disease and their interaction[J]. J Clin Hepatol (临床肝胆病杂志), 2022, 38: 902-907.

[31]

Lv J, Jiang Y, Zhang X, et al. Research progress of non-alcoholic fatty liver disease in traditional Chinese medicine[J]. Shanghai J Tradit Chin Med (上海中医药杂志), 2017, 51: 238-241.

[32]

Sun LW, Huang MZ. The effect of Danshen on the non-alcoholic fatty liver rats MDA, SOD, TNF and Leptin[J]. J Zhejiang Chin Med Univ (浙江中医药大学学报), 2007, 31: 696-698.

[33]

Zhang Y, Zhang J, Xin YN, et al. Effectiveness of Huganning tablet in the treatment of non-alcoholic steatoheoatitis[J]. Acta Acad Med Qingdao Univ (青岛大学医学院学报), 2017, 53: 100-102.

[34]

Chang SS, Zhou D, Meng GL, et al. Effect of Ganoderma lucidum polysaccharides on oxidative stress of hyperlipidemic fatty liver in rats[J]. Chin J Chin Mater Med (中国中药杂志), 2012, 37: 3102-3106.

[35]

Wu L, Xie YT. Effect of NF-κB on the pathogenic course of non-alcoholic fatty liver disease[J]. J Cent South Univ (中南大学学报), 2017, 42: 463-467.

[36]

Wang L, Li HJ. AGEs-RAGE signaling pathway in diabetic refractory wounds[J]. Chin J Burns Wounds Surf Ulcers (中国烧伤创疡杂志), 2015, 27: 406-409.

[37]

Huang N, Li WJ, An LG, et al. The function of FoxO1 and its relationship with human disease[J]. Chin Bull Life Sci (生命科学), 2012, 24: 334-339.

[38]

Matsumoto M, Han S, Kitamura T, et al. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism[J]. J Clin Invest, 2006, 116: 2464-2472.

[39]

Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism[J]. Nat Cell Biol, 2011, 13: 1016-1023.

[40]

Harish S, Ashok MS, Khanam T. Serine 27, a human retinoid X receptor a residue, phosphorylated by protein kinase A is essential for cyclicAMP-mediated downregulation of RXRα function[J]. Biochem Biophys Rec Commun, 2000, 279: 853-857.

[41]

Washburn DG, Hoang TH, Campobasso N, et al. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore[J]. Bioorg Med Chem Lett, 2009, 19: 1097-1100.

[42]

Tsutsumi T, Suzuki T, Shimoike T, et al. Interaction of hepatitis C virus core protein with retinoid X receptor α modulates its transcriptional activity[J]. Hepatology, 2002, 35: 937-946.

[43]

Qiu CH, Hou G, Huang DN. Molecular mechanism of TNF-α signal transduction[J]. Chin J Biochem Mol Biol (中国生物化学与分子生物学报), 2007, 23: 430-435.

[44]

Liu YB, Hu XF. Molecular mechanism of GSK-3β in tumor cells[J]. Chin J Biochem Mol Biol (中国生物化学与分子生物学报), 2020, 36: 259-266.

[45]

Liu MM, Ye DY. Advance in study of glycogen synthase kinase-3β and its inhibitors[J]. Prog Pharm Sci (药学进展), 2009, 33: 4145-4151.

[46]

Chi YJ, Li J, Guan YF, et al. PI3K/Akt signaling axis in regulation of glucose homeostasis[J]. Chin J Biochem Mol Biol (中国生物化学与分子生物学报), 2010, 26: 879-885.

[47]

Balasuriya N, McKenna M, Liu XG, et al. Phosphorylation-dependent inhibition of Akt1[J]. Genes, 2018, 9: 450.

[48]

Yang J, Chu P, Xiong YH, et al. Computer-aided drug design using in the modernization of traditional Chinese medicine[J]. World Clin Drugs (世界临床医药), 2009, 30: 615-619.

[49]

Qiao LS, Zhang YL. Application of CADD on multi-target drug R & D in natural products[J]. Chin J Chin Mater Med (中国中药杂志), 2014, 39: 1951-1955.

[50]

King E, Aitchison E, Li H, et al. Recent developments in free energy calculations for drug discovery[J]. Front Mol Biosci, 2021, 8: 712085.

[51]

Rastelli G, Del Rio A, Degliesposti G, et al. Fast and accurate predictions of binding free energies using MM-PBSA and MM-GBSA[J]. J Comput Chem, 2010, 31: 797-810.

2023年第58卷第3期

PDF下载

229

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2022-1046

接收时间：2022-09-07
首发时间：2025-11-21
出版时间：2023-03-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2022-09-07
修回日期：2022-10-02

基金

国家自然科学基金资助项目(82060627)

广西自然科学基金项目(2020GXNSFAA159149)

广西研究生教育创新计划项目(YCSW2022367)

作者信息

桂林医学院药学院, 广西桂林 541199

通讯作者:

*余启明, Tel: 86-773-2303428, E-mail: qm_yu19@glmc.edu.cn;

谭相端, E-mail: tandy@glmc.edu.cn

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2022-1046

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

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

关闭全屏

BibTeX
EndNote
RefWorks
TxT

No.	Compound	MW/g·mol^-1
Salvia miltiorrhiza
DS1	Trijuganone B	280.34
DS2	Poriferasterol	412.77
DS3	Clionasterol	414.79
DS4	Isoimperatorin	270.30
DS5	Sugiol	300.48
DS6	Dehydrotanshinone Ⅱ A	292.35
DS7	Baicalin	446.39
DS8	Digallic acid	322.24
DS9	α-Amyrin	426.80
DS10	Arucadiol	298.41
DS11	2-Isopropyl-8-methylphenanthrene-3, 4-dione	264.34
DS12	3α-Hydroxytanshinone Ⅱ A	310.37
DS13	Tournefolic acid A	312.29
DS14	4-Methylenemiltirone	266.36
DS15	2-(4-Hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-7-methoxy-3-benzofurancarboxaldehyde	356.40
DS16	6-o-Syringyl-8-o-acetyl shanzhiside methyl ester	628.64
DS17	Formyltanshinone	290.28
DS18	3-β-Hydroxymethyllenetanshiquinone	294.32
DS19	Methylenetanshinquinone	278.32
DS20	Przewalskin A	398.49
DS21	Przewalskin B	330.46
DS22	Przewaquinone B	292.30
DS23	Przewaquinone C	296.34
DS24	(6S, 7R)-6, 7-Dihydroxy-1, 6-dimethyl-8, 9-dihydro-7H-naphtho[8, 7-g]benzofuran-10, 11-dione	312.34
DS25	Przewaquinone F	312.34
DS26	Sclareol	308.56
DS27	Tanshinaldehyde	308.35
DS28	Danshenol B	354.48
DS29	Danshenol A	336.41
DS30	Salvilenone	292.40
DS31	Cryptotanshinone	296.39
DS32	Dan-shexinkum D	336.41
DS33	Danshenspiroketallactone	282.36
DS34	Deoxyneocryptotanshinone	298.41
DS35	Dihydrotanshinlactone	266.31
DS36	Dihydrotanshinone Ⅰ	278.32
DS37	Epidanshenspiroketallactone	284.38
DS38	Ferruginol	286.50
DS39	Isocryptotanshi-none	296.39
DS40	Isotanshinone Ⅱ A	294.37
DS41	Manool	290.50
DS42	Microstegiol	298.46
DS43	Miltionone Ⅰ	312.39
DS44	Miltionone Ⅱ	312.39
DS45	Miltipolone	300.43
DS46	Miltirone	282.41
DS47	Miltirone Ⅱ	272.32
DS48	Neocryptotanshinone Ⅱ	270.35
DS49	Neocryptotanshinone	314.41
DS50	Nortanshinone	280.29
DS51	Prolithospermic acid	314.31
DS52	(2R)-3-(3, 4-Dihydroxyphenyl)-2-[(Z)-3-(3, 4-dihydroxyphenyl)acryloyl]oxy-propionic acid	360.34
DS53	(Z)-3-[2-[(E)-2-(3, 4-Dihydroxyphenyl)vinyl]-3, 4-dihydroxy-phenyl]acrylic acid	314.31
DS54	Salvianolic acid G	340.30
DS55	Salvianolic acid J	538.49
DS56	Salvilenone Ⅰ	270.40
DS57	Salviolone	268.38
DS58	Tanshindiol A	312.34
DS59	Tanshindiol B	312.34
DS60	Przewaquinone E	312.34
DS61	Tanshinone Ⅱ A	294.37
DS62	Tanshinone Ⅱ B	310.37
DS63	Tanshinone Ⅵ	296.34
DS64	Salvianolic acid B	718.60
Ganoderma lucidum
LZ1	(+)-Ganoderic acid Mf	512.80
LZ2	(+)-Methyl ganolucidate A	514.77
LZ3	Methyl lucidenate F	470.66
LZ4	22, 23-Dimethylene ganodermic acid S	578.86
LZ5	22β-Acetoxy-3α, 15α-dihydroxylanosta-7, 9(11), 24-trien-26-oic acid	528.90
LZ6	Campesta-7, 22E-dien-3beta-ol	398.74
LZ7	5α-Lanosta-7, 9(11), 24-triene-15α, 26-dihydroxy-3-one	454.76
LZ8	Epoxyganoderiol A	472.78
LZ9	Epoxyganoderiol B	454.76
LZ10	Epoxyganoderiol C	456.78
LZ11	Ergosta-4, 6, 8(14), 22-tetraene-3-one	406.71
LZ12	Ergosta-4, 7, 22-trien-3, 6-dione	408.68
LZ13	Ergosta-7, 22-dien-3β-yl palmitate	637.20
LZ14	Ergosta-7, 22-dien-3β, 5α, 6α-triol	430.74
LZ15	Ergosta-7, 22-diene-3β-yl linoleate	661.22
LZ16	Ergosta-7, 22-diene-3β-yl palmitate	637.20
LZ17	Ergosta-7, 22-diene-3β-yl pentadecanoate	623.17
LZ18	Ergosta-7, 9(11), 22-trien-3β, 5α, 6α-triol	442.75
LZ19	Peroxyergosterol	428.72
LZ20	Ganoderal B	440.73
LZ21	Ganoderan B	454.76
LZ22	Ganoderic acid beta	500.74
LZ23	Ganoderic acid DM	468.74
LZ24	Ganodermic acid R	554.84
LZ25	Ganoderic acid Mi	528.85
LZ26	(E, 5S, 6S)-5-Acetoxy-6-[(3R, 5R, 10S, 13R, 14R, 17R)-3-hydroxy-4, 4, 10, 13, 14-pentamethyl-2, 3, 5, 6, 12, 15, 16, 17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylhept-2-enoic acid	512.80
LZ27	Ganoderic acid TQ	524.81
LZ28	Ganoderic acid TR	468.74
LZ29	Ganoderic acid Ⅴ	528.80
LZ30	Ganoderic acid Ⅴ1	512.75
LZ31	Ganoderic acid X	512.80
LZ32	Ganoderic acid Y	454.76
LZ33	Ganoderic acid Z	456.78
LZ34	Ganoderic aldehyde A	454.76
LZ35	Ganoderiol F	454.76
LZ36	Ganodermanondiol	456.78
LZ37	Ganodermatriol	456.78
LZ38	Ganodermenonol	438.76
LZ39	Ganodermic acid T-Q	512.80
LZ40	Ganodermic acid T-O	512.80
LZ41	Ganolucidic acid E	484.74
LZ42	Ganosporelactone B	530.72
LZ43	Lanosta-7, 9(11), 24-trien-15α-acetoxy-3α-hydroxy-23-oxo-26-oic acid	526.78
LZ44	Lanosta-7, 9(11), 24-trien-3α-acetoxy-15α-hydroxy-23-oxo-26-oic acid	526.78
LZ45	Lanosta-7, 9(11), 24-trien-3α-acetoxy-26-oic acid	496.80
LZ46	Lucialdehyde A	438.76
LZ47	Lucialdehyde B	452.74
LZ48	Lucialdehyde C	454.76
LZ49	Lucidenic acid A	458.65
LZ50	Lucidone A	402.58
LZ51	Lucidumol A	458.80
LZ52	Methyl ganoderic acid DM	482.77
LZ53	Methyl ganoderic acid TR	482.77
LZ54	Methyl lucidenate Q	474.70
LZ55	Cerevisterol	430.74
LZ56	Ergosta-7, 22E-dien-3β-ol	398.74
LZ57	Oleanic acid	456.70
Sedum sarmentosum Bunge
CP1	Liquiritigenin	256.27
CP2	Isorhamnetin	316.28
CP3	Sarmentosine	275.29
CP4	δ-Amyrone	424.70
CP5	Kaempferide	300.26
CP6	Sedumoside Ⅰ	388.50
CP7	Tricin	330.29
Polygoni Cuspidati Rhizoma et Radix
HZ1	6, 8-Dihydroxy-7-methoxyxanthone	258.24
HZ2	Physovenine	262.34
HZ3	Picralinal	366.45
HZ4	Physciondiglucoside	608.60
HZ5	Rhein	284.23
HZ6	Torachrysone-8-O-β-D-(6'-oxayl)-glucoside	480.46
HZ7	(+)-Catechin	290.29
HZ8	Resveratrol	228.26
HZ9	Polydatin	390.42
HZ10	Emodin	270.24
Multi-drug
A1	β-Sitosterol	414.79
A2	Luteolin	286.25
A3	Quercetin	302.25

No.

Compound

MW/g·mol^-1

Salvia miltiorrhiza

DS1

Trijuganone B

280.34

DS2

Poriferasterol

412.77

DS3

Clionasterol

414.79

DS4

Isoimperatorin

270.30

DS5

Sugiol

300.48

DS6

Dehydrotanshinone Ⅱ A

292.35

DS7

Baicalin

446.39

DS8

Digallic acid

322.24

DS9

α-Amyrin

426.80

DS10

Arucadiol

298.41

DS11

2-Isopropyl-8-methylphenanthrene-3, 4-dione

264.34

DS12

3α-Hydroxytanshinone Ⅱ A

310.37

DS13

Tournefolic acid A

312.29

DS14

4-Methylenemiltirone

266.36

DS15

2-(4-Hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-7-methoxy-3-benzofurancarboxaldehyde

356.40

DS16

6-o-Syringyl-8-o-acetyl shanzhiside methyl ester

628.64

DS17

Formyltanshinone

290.28

DS18

3-β-Hydroxymethyllenetanshiquinone

294.32

DS19

Methylenetanshinquinone

278.32

DS20

Przewalskin A

398.49

DS21

Przewalskin B

330.46

DS22

Przewaquinone B

292.30

DS23

Przewaquinone C

296.34

DS24

(6S, 7R)-6, 7-Dihydroxy-1, 6-dimethyl-8, 9-dihydro-7H-naphtho[8, 7-g]benzofuran-10, 11-dione

312.34

DS25

Przewaquinone F

312.34

DS26

Sclareol

308.56

DS27

Tanshinaldehyde

308.35

DS28

Danshenol B

354.48

DS29

Danshenol A

336.41

DS30

Salvilenone

292.40

DS31

Cryptotanshinone

296.39

DS32

Dan-shexinkum D

336.41

DS33

Danshenspiroketallactone

282.36

DS34

Deoxyneocryptotanshinone

298.41

DS35

Dihydrotanshinlactone

266.31

DS36

Dihydrotanshinone Ⅰ

278.32

DS37

Epidanshenspiroketallactone

284.38

DS38

Ferruginol

286.50

DS39

Isocryptotanshi-none

296.39

DS40

Isotanshinone Ⅱ A

294.37

DS41

Manool

290.50

DS42

Microstegiol

298.46

DS43

Miltionone Ⅰ

312.39

DS44

Miltionone Ⅱ

312.39

DS45

Miltipolone

300.43

DS46

Miltirone

282.41

DS47

Miltirone Ⅱ

272.32

DS48

Neocryptotanshinone Ⅱ

270.35

DS49

Neocryptotanshinone

314.41

DS50

Nortanshinone

280.29

DS51

Prolithospermic acid

314.31

DS52

(2R)-3-(3, 4-Dihydroxyphenyl)-2-[(Z)-3-(3, 4-dihydroxyphenyl)acryloyl]oxy-propionic acid

360.34

DS53

(Z)-3-[2-[(E)-2-(3, 4-Dihydroxyphenyl)vinyl]-3, 4-dihydroxy-phenyl]acrylic acid

314.31

DS54

Salvianolic acid G

340.30

DS55

Salvianolic acid J

538.49

DS56

Salvilenone Ⅰ

270.40

DS57

Salviolone

268.38

DS58

Tanshindiol A

312.34

DS59

Tanshindiol B

312.34

DS60

Przewaquinone E

312.34

DS61

Tanshinone Ⅱ A

294.37

DS62

Tanshinone Ⅱ B

310.37

DS63

Tanshinone Ⅵ

296.34

DS64

Salvianolic acid B

718.60

Ganoderma lucidum

LZ1

(+)-Ganoderic acid Mf

512.80

LZ2

(+)-Methyl ganolucidate A

514.77

LZ3

Methyl lucidenate F

470.66

LZ4

22, 23-Dimethylene ganodermic acid S

578.86

LZ5

22β-Acetoxy-3α, 15α-dihydroxylanosta-7, 9(11), 24-trien-26-oic acid

528.90

LZ6

Campesta-7, 22E-dien-3beta-ol

398.74

LZ7

5α-Lanosta-7, 9(11), 24-triene-15α, 26-dihydroxy-3-one

454.76

LZ8

Epoxyganoderiol A

472.78

LZ9

Epoxyganoderiol B

454.76

LZ10

Epoxyganoderiol C

456.78

LZ11

Ergosta-4, 6, 8(14), 22-tetraene-3-one

406.71

LZ12

Ergosta-4, 7, 22-trien-3, 6-dione

408.68

LZ13

Ergosta-7, 22-dien-3β-yl palmitate

637.20

LZ14

Ergosta-7, 22-dien-3β, 5α, 6α-triol

430.74

LZ15

Ergosta-7, 22-diene-3β-yl linoleate

661.22

LZ16

Ergosta-7, 22-diene-3β-yl palmitate

637.20

LZ17

Ergosta-7, 22-diene-3β-yl pentadecanoate

623.17

LZ18

Ergosta-7, 9(11), 22-trien-3β, 5α, 6α-triol

442.75

LZ19

Peroxyergosterol

428.72

LZ20

Ganoderal B

440.73

LZ21

Ganoderan B

454.76

LZ22

Ganoderic acid beta

500.74

LZ23

Ganoderic acid DM

468.74

LZ24

Ganodermic acid R

554.84

LZ25

Ganoderic acid Mi

528.85

LZ26

(E, 5S, 6S)-5-Acetoxy-6-[(3R, 5R, 10S, 13R, 14R, 17R)-3-hydroxy-4, 4, 10, 13, 14-pentamethyl-2, 3, 5, 6, 12, 15, 16, 17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylhept-2-enoic acid

512.80

LZ27

Ganoderic acid TQ

524.81

LZ28

Ganoderic acid TR

468.74

LZ29

Ganoderic acid Ⅴ

528.80

LZ30

Ganoderic acid Ⅴ1

512.75

LZ31

Ganoderic acid X

512.80

LZ32

Ganoderic acid Y

454.76

LZ33

Ganoderic acid Z

456.78

LZ34

Ganoderic aldehyde A

454.76

LZ35

Ganoderiol F

454.76

LZ36

Ganodermanondiol

456.78

LZ37

Ganodermatriol

456.78

LZ38

Ganodermenonol

438.76

LZ39

Ganodermic acid T-Q

512.80

LZ40

Ganodermic acid T-O

512.80

LZ41

Ganolucidic acid E

484.74

LZ42

Ganosporelactone B

530.72

LZ43

Lanosta-7, 9(11), 24-trien-15α-acetoxy-3α-hydroxy-23-oxo-26-oic acid

526.78

LZ44

Lanosta-7, 9(11), 24-trien-3α-acetoxy-15α-hydroxy-23-oxo-26-oic acid

526.78

LZ45

Lanosta-7, 9(11), 24-trien-3α-acetoxy-26-oic acid

496.80

LZ46

Lucialdehyde A

438.76

LZ47

Lucialdehyde B

452.74

LZ48

Lucialdehyde C

454.76

LZ49

Lucidenic acid A

458.65

LZ50

Lucidone A

402.58

LZ51

Lucidumol A

458.80

LZ52

Methyl ganoderic acid DM

482.77

LZ53

Methyl ganoderic acid TR

482.77

LZ54

Methyl lucidenate Q

474.70

LZ55

Cerevisterol

430.74

LZ56

Ergosta-7, 22E-dien-3β-ol

398.74

LZ57

Oleanic acid

456.70

Sedum sarmentosum Bunge

CP1

Liquiritigenin

256.27

CP2

Isorhamnetin

316.28

CP3

Sarmentosine

275.29

CP4

δ-Amyrone

424.70

CP5

Kaempferide

300.26

CP6

Sedumoside Ⅰ

388.50

CP7

Tricin

330.29

Polygoni Cuspidati Rhizoma et Radix

HZ1

6, 8-Dihydroxy-7-methoxyxanthone

258.24

HZ2

Physovenine

262.34

HZ3

Picralinal

366.45

HZ4

Physciondiglucoside

608.60

HZ5

Rhein

284.23

HZ6

Torachrysone-8-O-β-D-(6'-oxayl)-glucoside

480.46

HZ7

(+)-Catechin

290.29

HZ8

Resveratrol

228.26

HZ9

Polydatin

390.42

HZ10

Emodin

270.24

Multi-drug

β-Sitosterol

414.79

Luteolin

286.25

Quercetin

302.25

No.	Uniprot	Gene	Target name	Degree
1	P19793	RXRA	Retinoic acid receptor RXR-alpha	32
2	P01375	TNF	Tumor necrosis factor	31
3	P49841	GSK3B	Glycogen synthase kinase-3 beta	22
4	P31749	AKT1	Serine/threonine-protein kinase 1	22
5	P45983	MAPK8	Mitogen-activated protein kinase 8	21
6	P05412	JUN	Transcription factor Jun	19
7	P42336	PIK3CA	Phosphatidylinositol 4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform	17
8	Q13133	NR1H3	Oxysterols receptor LXR-alpha	16
9	P45984	MAPK9	Mitogen-activated protein kinase 9	16
10	P05231	IL6	Interleukin-6	15
11	P10145	CXCL8	Interleukin-8	11
12	P01584	IL1B	Interleukin-1 beta	10
13	P37231	PPARG	Peroxisome proliferator-activated receptor gamma	8
14	Q07869	PPARA	Peroxisome proliferator-activated receptor alpha	8
15	P06213	INSR	Insulin receptor	7
16	P35568	IRS1	Insulin receptor substrate 1	6
17	P01583	IL1A	Interleukin-1 alpha	5
18	P36956	SREBF1	Sterol regulatory element-binding protein 1	5
19	Q96A54	ADIPOR1	Adiponectin receptor protein 1	5
20	Q86V24	ADIPOR2	Adiponectin receptor protein 2	5
21	P49327	FASN	Fatty acid synthase	4
22	P35638	DDIT3	DNA damage-inducible transcript 3 protein	3
23	P05198	EIF2S1	Eukaryotic translation initiation factor 2 subunit 1	2
24	Q96RI1	NR1H4	Bile acid receptor	2

No.

Uniprot

Gene

Target name

Degree

P19793

RXRA

Retinoic acid receptor RXR-alpha

P01375

TNF

Tumor necrosis factor

P49841

GSK3B

Glycogen synthase kinase-3 beta

P31749

AKT1

Serine/threonine-protein kinase 1

P45983

MAPK8

Mitogen-activated protein kinase 8

P05412

JUN

Transcription factor Jun

P42336

PIK3CA

Phosphatidylinositol 4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform

Q13133

NR1H3

Oxysterols receptor LXR-alpha

P45984

MAPK9

Mitogen-activated protein kinase 9

P05231

IL6

Interleukin-6

P10145

CXCL8

Interleukin-8

P01584

IL1B

Interleukin-1 beta

P37231

PPARG

Peroxisome proliferator-activated receptor gamma

Q07869

PPARA

Peroxisome proliferator-activated receptor alpha

P06213

INSR

Insulin receptor

P35568

IRS1

Insulin receptor substrate 1

P01583

IL1A

Interleukin-1 alpha

P36956

SREBF1

Sterol regulatory element-binding protein 1

Q96A54

ADIPOR1

Adiponectin receptor protein 1

Q86V24

ADIPOR2

Adiponectin receptor protein 2

P49327

FASN

Fatty acid synthase

P35638

DDIT3

DNA damage-inducible transcript 3 protein

P05198

EIF2S1

Eukaryotic translation initiation factor 2 subunit 1

Q96RI1

NR1H4

Bile acid receptor

Ingredient	-CDOCKER ENERGY/kcal·mol^-1
Co-crystallized ligand	34.474 6	18.688 0	30.333 0	29.126 0
Isorhamnetin	60.862 3	30.908 4	51.046 3	41.329 5
Salvianolic acid B	20.195 8	63.062 1	70.472 6	58.569 4
Emodin	39.100 8	32.491 2	52.176 7	37.718 6
Resveratrol	43.418 5	26.458 1	42.687 5	29.655 7
Rhein	45.940 7	26.458 1	48.422 7	32.405 8

Ingredient

-CDOCKER ENERGY/kcal·mol^-1

RXRA

TNF

GSK3B

AKT1

Co-crystallized ligand

34.474 6

18.688 0

30.333 0

29.126 0

Isorhamnetin

60.862 3

30.908 4

51.046 3

41.329 5

Salvianolic acid B

20.195 8

63.062 1

70.472 6

58.569 4

Emodin

39.100 8

32.491 2

52.176 7

37.718 6

Resveratrol

43.418 5

26.458 1

42.687 5

29.655 7

Rhein

45.940 7

26.458 1

48.422 7

32.405 8

Ingredient	MW/g·mol^-1	LogP	HBD	HBA	PSA/Å	Rotatable bond	Water solubility/log mol·L^-1	Caco-2 permeability/log P_app	Intestinal absorption/%	CYP2D6 inhibitor	Hepatotoxicity
Isorhamnetin	316.26	2.291	4	7	128.792	2	-3.000	-0.003	76.014	No	No
Salvianolic acid B	718.62	3.334	9	14	292.421	12	-2.892	-1.570	9.902	No	No
Emodin	270.24	1.887	3	5	113.283	0	-2.892	1.613	85.629	No	No
Resveratrol	228.24	2.973	3	3	98.911	2	-3.178	1.170	90.935	No	No
Rhein	284.22	1.571	3	5	117.445	1	-2.843	-0.241	55.000	No	No

Ingredient

MW/g·mol^-1

LogP

HBD

HBA

PSA/Å

Rotatable bond

Water solubility/log mol·L^-1

Caco-2 permeability/log P_app

Intestinal absorption/%

CYP2D6 inhibitor

Hepatotoxicity

Isorhamnetin

316.26

2.291

128.792

-3.000

-0.003

76.014

Salvianolic acid B

718.62

3.334

292.421

-2.892

-1.570

9.902

Emodin

270.24

1.887

113.283

-2.892

1.613

85.629

Resveratrol

228.24

2.973

98.911

-3.178

1.170

90.935

Rhein

284.22

1.571

117.445

-2.843

-0.241

55.000