药学学报

Group	Body weight/g	TC/mmol·L^-1	TG/mmol·L^-1	HDL-C/mmol·L^-1	LDL-C/mmol·L^-1	AST/U·L^-1	ALT/U·L^-1
NC	471.8 ± 16.90	1.150 ± 0.092 74	0.150 0 ± 0.047 61	0.935 0 ± 0.069 52	0.410 0 ± 0.049 67	84.00 ± 7.79	29.75 ± 2.062
DC	322.0 ± 12.83^###	1.363 ± 0.145 70^#	0.367 5 ± 0.020 62^###	0.437 5 ± 0.066 52^###	0.860 0 ± 0.075 28^###	110.8 ± 8.88^##	62.00 ± 8.602^###
RSG	383.0 ± 7.70^***	1.185 ± 0.023 80	0.215 0 ± 0.031 09^***	0.812 5 ± 0.091 06^***	0.445 0 ± 0.031 09^***	85.75 ± 7.50^**	35.25 ± 5.909^***
L	350.3 ± 21.96	1.285 ± 0.096 78	0.215 0 ± 0.031 09^**	0.702 5 ± 0.066 02^***	0.622 5 ± 0.087 32^***	93.00 ± 14.72	45.50 ± 8.347^*
H	365.8 ± 24.60^**	1.245 ± 0.068 07	0.255 0 ± 0.041 23^***	0.797 5 ± 0.086 55^***	0.515 0 ± 0.064 55^***	91.00 ± 11.92^*	40.00 ± 10.200^**

Group	Body weight/g	TC/mmol·L^-1	TG/mmol·L^-1	HDL-C/mmol·L^-1	LDL-C/mmol·L^-1	AST/U·L^-1	ALT/U·L^-1
NC	471.8 ± 16.90	1.150 ± 0.092 74	0.150 0 ± 0.047 61	0.935 0 ± 0.069 52	0.410 0 ± 0.049 67	84.00 ± 7.79	29.75 ± 2.062
DC	322.0 ± 12.83^###	1.363 ± 0.145 70^#	0.367 5 ± 0.020 62^###	0.437 5 ± 0.066 52^###	0.860 0 ± 0.075 28^###	110.8 ± 8.88^##	62.00 ± 8.602^###
RSG	383.0 ± 7.70^***	1.185 ± 0.023 80	0.215 0 ± 0.031 09^***	0.812 5 ± 0.091 06^***	0.445 0 ± 0.031 09^***	85.75 ± 7.50^**	35.25 ± 5.909^***
L	350.3 ± 21.96	1.285 ± 0.096 78	0.215 0 ± 0.031 09^**	0.702 5 ± 0.066 02^***	0.622 5 ± 0.087 32^***	93.00 ± 14.72	45.50 ± 8.347^*
H	365.8 ± 24.60^**	1.245 ± 0.068 07	0.255 0 ± 0.041 23^***	0.797 5 ± 0.086 55^***	0.515 0 ± 0.064 55^***	91.00 ± 11.92^*	40.00 ± 10.200^**

No.	Name	OB	DL	Compound type
M01	Baicalin	41.24	0.24	Flavonoids
M02	Calycosin	47.73	0.24
M03	Isorhamnetin	52.29	0.73
M04	Kaempferol	62.13	0.24
M05	Quercetin	45.06	0.28
M06	Quercetin-3-O-galactoside	68.28	0.19
M07	5, 8, 3', 4'-Tetrahydroxy-7-methoxyflavone	49.91	0.30
M08	5, 8, 4'-Trihydroxy-7, 3'-dimethoxyflavone	63.49	0.34
M09	Baicalin methyl ester	39.69	0.79
M10	Isorhamnetin-3-O-β-D-glucoside	60.00	0.74
M11	8-O-Methylsenecioylaustricin	64.08	0.41	Terpenoids
M12	Daucosterol-qt	36.91	0.75
M13	Inulicin	30.60	0.22
M14	Lactucin	29.81	0.22
M15	Lactupicrin	18.93	0.71
M16	Stigmasterol	64.91	0.75
M17	11β, 13-Dihydrolactucin	39.56	0.22
M18	Taraxerone	64.59	0.19
M19	β-Sitosterol	36.91	0.75
M20	8-O-Senecioylaustricin	104.45	0.62
M21	Lupeol acetate	52.29	0.73
M22	1, 3-Dicaffeoylquinic acid	52.22	0.63	Phenylpropanoid
M23	3, 4-Dicaffeoylquinic acid	71.29	0.69
M24	3, 5-Dicaffeoylquinic acid	50.06	0.69
M25	4, 4'-Dimethyl-1, 7-heptane diacid	41.83	0.64	Organic acids
M26	Carnaubic acid	41.83	0.64
M27	2-Furanmethanol-(5'→11)-1, 3-cyclopentadiene-[5, 4-c]-1H-cinnoline	74.20	0.28	Alkaloids
M28	Corn riboflavin	56.56	0.76
M28-qt	Corn riboflavin-qt	30.81	0.19

No.	Name	OB	DL	Compound type
M01	Baicalin	41.24	0.24	Flavonoids
M02	Calycosin	47.73	0.24
M03	Isorhamnetin	52.29	0.73
M04	Kaempferol	62.13	0.24
M05	Quercetin	45.06	0.28
M06	Quercetin-3-O-galactoside	68.28	0.19
M07	5, 8, 3', 4'-Tetrahydroxy-7-methoxyflavone	49.91	0.30
M08	5, 8, 4'-Trihydroxy-7, 3'-dimethoxyflavone	63.49	0.34
M09	Baicalin methyl ester	39.69	0.79
M10	Isorhamnetin-3-O-β-D-glucoside	60.00	0.74
M11	8-O-Methylsenecioylaustricin	64.08	0.41	Terpenoids
M12	Daucosterol-qt	36.91	0.75
M13	Inulicin	30.60	0.22
M14	Lactucin	29.81	0.22
M15	Lactupicrin	18.93	0.71
M16	Stigmasterol	64.91	0.75
M17	11β, 13-Dihydrolactucin	39.56	0.22
M18	Taraxerone	64.59	0.19
M19	β-Sitosterol	36.91	0.75
M20	8-O-Senecioylaustricin	104.45	0.62
M21	Lupeol acetate	52.29	0.73
M22	1, 3-Dicaffeoylquinic acid	52.22	0.63	Phenylpropanoid
M23	3, 4-Dicaffeoylquinic acid	71.29	0.69
M24	3, 5-Dicaffeoylquinic acid	50.06	0.69
M25	4, 4'-Dimethyl-1, 7-heptane diacid	41.83	0.64	Organic acids
M26	Carnaubic acid	41.83	0.64
M27	2-Furanmethanol-(5'→11)-1, 3-cyclopentadiene-[5, 4-c]-1H-cinnoline	74.20	0.28	Alkaloids
M28	Corn riboflavin	56.56	0.76
M28-qt	Corn riboflavin-qt	30.81	0.19

Protein	PDB ID	Compound	Affinity/kcal·mol ^-1	Amino acid
PTGS2	4PH9	M05	-8.4	TYR-356, PHE-519, TYR-386, HIS-90
INSR	5E1S	M02	-7.4	MET 1079, LEU-1002
INSR	5E1S	M03	-8.2	MET-1079
INSR	5E1S	M04	-7.6	LEU-1002
INSR	5E1S	M05	-7.6	LEU-1002, MET-1079, ASP-1150
INSR	5E1S	M06	-8.5	ASP-1150, GLY-1003
INSR	5E1S	M08	-7.9	ASP-1150
INSR	5E1S	M09	-8.9	ASP-1150, MET-1079
PIK3R1	5XGH	M02	-7.2	VAL-851, SER-854, GLU-849
PIK3R1	5XGH	M03	-7.7	TYR-836, ASN-170
PIK3R1	5XGH	M04	-7.7	LEU-814
PIK3R1	5XGH	M05	-7.9	TYR-836, ASP-626
PIK3R1	5XGH	M06	-8.7	CYS-838, HIS-670, GLN-815, GLN-630, ILE-633, ARG-818, ASN-170
PIK3R1	5XGH	M07	-8.2	TYR-836, VAL-851
PIK3R1	5XGH	M08	-8.1	TYR-836, ASP-933, VAL-851
PIK3R1	5XGH	M09	-8.4	CYS-838, TYR-836
PIK3R1	5XGH	M12	-8.3	-
PIK3R1	5XGH	M13	-7.0	-
PIK3R1	5XGH	M15	-8.8	CYS-838
PIK3R1	5XGH	M17	-7.1	PRO-835, ARG-818, GLN-630, CYS-838
PIK3R1	5XGH	M19	-7.9	GLU-849
PIK3R1	5XGH	M20	-8.2	ARG-818
PIK3R1	5XGH	M21	-9.0	-
PIK3R1	5XGH	M22	-8.5	TYR-836, CYS-838, ASN-756, ASN-170
PIK3R1	5XGH	M27	-8.6	TYR-836, VAL-851
HTR2A	6A94	M01	-7.6	LEU-229, CYS-227
HTR2A	6A94	M03	-9.0	SER-239
HTR2A	6A94	M06	-7.5	TYR-370, LEU-229, VAL-156, THR-160
HTR2A	6A94	M08	-8.2	ASN-343, TYR-370
HTR2A	6A94	M09	-6.8	ASN-363, TYR-139
HTR2A	6A94	M10	-6.1	ASN-363, ASP-356
HTR2A	6A94	M11	-8.3	ASN-343, SER-239
HTR2A	6A94	M16	-8.0	-
HTR2A	6A94	M23	-9.0	SER-242, THR-160, ILE-206
HTR2A	6A94	M24	-10.9	LEU-229, TRP-367, SER-131, THR-160
HTR2A	6A94	M25	-5.7	VAL-235
G6PD	6E08	M07	-7.0	TRP-509, ASP-421
G6PD	6E08	M12	-7.8	-
G6PD	6E08	M13	-5.7	LYS-366, ARG-370
G6PD	6E08	M17	-6.3	ARG-487
G6PD	6E08	M19	-7.7	-
G6PD	6E08	M21	-7.4	-
G6PD	6E08	M22	-9.3	ARG-370, LYS-366, THR-236
G6PD	6E08	M28	-6.6	ASP-421, ARG-370, ARG-487

Protein	PDB ID	Compound	Affinity/kcal·mol ^-1	Amino acid
PTGS2	4PH9	M05	-8.4	TYR-356, PHE-519, TYR-386, HIS-90
INSR	5E1S	M02	-7.4	MET 1079, LEU-1002
INSR	5E1S	M03	-8.2	MET-1079
INSR	5E1S	M04	-7.6	LEU-1002
INSR	5E1S	M05	-7.6	LEU-1002, MET-1079, ASP-1150
INSR	5E1S	M06	-8.5	ASP-1150, GLY-1003
INSR	5E1S	M08	-7.9	ASP-1150
INSR	5E1S	M09	-8.9	ASP-1150, MET-1079
PIK3R1	5XGH	M02	-7.2	VAL-851, SER-854, GLU-849
PIK3R1	5XGH	M03	-7.7	TYR-836, ASN-170
PIK3R1	5XGH	M04	-7.7	LEU-814
PIK3R1	5XGH	M05	-7.9	TYR-836, ASP-626
PIK3R1	5XGH	M06	-8.7	CYS-838, HIS-670, GLN-815, GLN-630, ILE-633, ARG-818, ASN-170
PIK3R1	5XGH	M07	-8.2	TYR-836, VAL-851
PIK3R1	5XGH	M08	-8.1	TYR-836, ASP-933, VAL-851
PIK3R1	5XGH	M09	-8.4	CYS-838, TYR-836
PIK3R1	5XGH	M12	-8.3	-
PIK3R1	5XGH	M13	-7.0	-
PIK3R1	5XGH	M15	-8.8	CYS-838
PIK3R1	5XGH	M17	-7.1	PRO-835, ARG-818, GLN-630, CYS-838
PIK3R1	5XGH	M19	-7.9	GLU-849
PIK3R1	5XGH	M20	-8.2	ARG-818
PIK3R1	5XGH	M21	-9.0	-
PIK3R1	5XGH	M22	-8.5	TYR-836, CYS-838, ASN-756, ASN-170
PIK3R1	5XGH	M27	-8.6	TYR-836, VAL-851
HTR2A	6A94	M01	-7.6	LEU-229, CYS-227
HTR2A	6A94	M03	-9.0	SER-239
HTR2A	6A94	M06	-7.5	TYR-370, LEU-229, VAL-156, THR-160
HTR2A	6A94	M08	-8.2	ASN-343, TYR-370
HTR2A	6A94	M09	-6.8	ASN-363, TYR-139
HTR2A	6A94	M10	-6.1	ASN-363, ASP-356
HTR2A	6A94	M11	-8.3	ASN-343, SER-239
HTR2A	6A94	M16	-8.0	-
HTR2A	6A94	M23	-9.0	SER-242, THR-160, ILE-206
HTR2A	6A94	M24	-10.9	LEU-229, TRP-367, SER-131, THR-160
HTR2A	6A94	M25	-5.7	VAL-235
G6PD	6E08	M07	-7.0	TRP-509, ASP-421
G6PD	6E08	M12	-7.8	-
G6PD	6E08	M13	-5.7	LYS-366, ARG-370
G6PD	6E08	M17	-6.3	ARG-487
G6PD	6E08	M19	-7.7	-
G6PD	6E08	M21	-7.4	-
G6PD	6E08	M22	-9.3	ARG-370, LYS-366, THR-236
G6PD	6E08	M28	-6.6	ASP-421, ARG-370, ARG-487

基于系统药理学的毛菊苣醇提物治疗2型糖尿病伴随非酒精性脂肪肝作用及机制研究

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秦惠玉 ¹ , 张彤 ¹^,² , 王忠英 ¹ , 陈文 ¹ , 韩博 ¹^,^*

药学学报 | 研究论文 2019,54(11): 2019-2030

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药学学报 |研究论文 2019 , 54 (11) : 2019 -2030

基于系统药理学的毛菊苣醇提物治疗2型糖尿病伴随非酒精性脂肪肝作用及机制研究

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秦惠玉¹, 张彤¹^,², 王忠英¹, 陈文¹, 韩博¹^,^*

作者信息

1.石河子大学药学院, 新疆石河子 832002

2.北京科兴生物制品有限公司, 北京 100085

通讯作者:

*韩博, Tel: 86-993-2613049, E-mail: hanbodexinxiang@163.com

The action and mechanism of ethanol extract of Cichorium glandulosum on type 2 diabetes mellitus accompanied with nonalcoholic fatty liver disease based on systems pharmacology

Hui-yu QIN¹, Tong ZHANG¹^,², Zhong-ying WANG¹, Wen CHEN¹, Bo HAN¹^,^*

Affiliations

1. School of Pharmacy, Shihezi University, Shihezi 832002, China

2. Sinovac Biotech CO., Ltd., Beijing 100085, China

出版时间: 2019-11-12 doi: 10.16438/j.0513-4870.2019-0114

文章导航

摘要

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毛菊苣在维吾尔族民间被用于治疗非酒精性脂肪肝（non-alcoholic fatty liver disease，NAFLD）和2型糖尿病（type 2 diabetes mellitus），但其治疗2型糖尿病伴随非酒精性脂肪肝（T2DM-NAFLD）的作用机制尚不明确。本研究通过动物实验对毛菊苣提取物治疗T2DM-NAFLD的作用进行研究（本动物实验经石河子大学医学院第一附属医院实验动物伦理审查委员会批准）；运用系统药理学筛选并预测毛菊苣治疗T2DM-NAFLD的靶点、通路和疾病，构建和分析化合物-靶点-通路和化合物-靶点-疾病关系网络。动物实验表明，毛菊苣提取物可改善T2DM-NAFLD大鼠的血糖血脂水平，增加糖耐量并减轻肝损伤。通过系统药理学筛选得到毛菊苣中29个可能的活性成分、198个靶点，其中涉及T2DM的靶点106个，涉及NAFLD的靶点88个，T2DM和NAFLD共有的靶点56个，这些靶点主要参与代谢通路、钙信号通路、PI3K/Akt信号通路、cAMP通路、MAPK通路等，与胰岛素抵抗和炎症有关。毛菊苣可能是治疗T2DM-NAFLD的候选草药，本工作为研究多靶点植物药治疗多种疾病提供了系统药理学角度的参考。

关键词

毛菊苣 / 2型糖尿病伴随非酒精性脂肪肝 / 系统药理学 / 活性成分

Abstract

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Cichorium glandulosum has been used to treat non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) in Uyghur folk medicine. The mechanism of Cichorium glandulosum (CG) on type 2 diabetes mellitus accompanied with non-alcoholic fatty liver disease (T2DM-NAFLD) remains unclear. The effect of CG extraction on T2DM-NAFLD was determined in animal experiments here (all the experiments here were approved by the Animal Care Committee of the First Affiliated Hospital of the Medical College, Shihezi University). The mechanism of CG for treatment of T2DM-NAFLD was predicted and verified based on systems pharmacology. Based on the active compounds of CG on T2DM-NAFLD, T2DM and NAFLD-related targets, pathways and diseases were screened and predicted. Active compounds-targets, compounds-targets-pathways and compounds-targets-diseases were constructed and analyzed. The results of animal experiments showed that CG extraction can reduce the levels of blood glucose and blood lipid in T2DM-NAFLD rats. In addition, it can improve the glucose tolerance and relieve liver injury. Total 29 active compounds and 198 targets were screened by systems pharmacology, of which 106 targets were involved in T2DM, 88 were involved in NAFLD, and 56 targets were common between T2DM and NAFLD, mainly related to insulin resistance and inflammation. These 198 targets include those in metabolic pathways, calcium pathway, PI3K/Akt pathway, cAMP pathway, and MAPK pathway. Our study confirmed that CG can be potential phytomedicine for treatment of T2DM-NAFLD. This work provides a reference for studying the treatment of multiple diseases using multiple-targets phytomedicine in systems pharmacology.

Key words

Cichorium glandulosum / type 2 diabetes mellitus accompanied with non-alcoholic fatty liver disease / systems pharmacology / active compound

引用本文

秦惠玉, 张彤, 王忠英, 陈文, 韩博. 基于系统药理学的毛菊苣醇提物治疗2型糖尿病伴随非酒精性脂肪肝作用及机制研究. 药学学报, 2019 , 54 (11) : 2019 -2030 . DOI: 10.16438/j.0513-4870.2019-0114

Hui-yu QIN, Tong ZHANG, Zhong-ying WANG, Wen CHEN, Bo HAN. The action and mechanism of ethanol extract of Cichorium glandulosum on type 2 diabetes mellitus accompanied with nonalcoholic fatty liver disease based on systems pharmacology[J]. Acta Pharmaceutica Sinica, 2019 , 54 (11) : 2019 -2030 . DOI: 10.16438/j.0513-4870.2019-0114

正文

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在糖尿病(T2DM)人群中非酒精性脂肪肝(NAFLD)的发病率约为70%^[1]。目前治疗T2DM-NAFLD的药物如胰岛素增敏剂和噻唑烷二酮类对减轻肝脏脂肪变性、坏死性炎症或肝纤维化的效果并不显著^[2]; 降脂药(如他汀类)和抗氧化剂(如维生素E)对其有一定疗效, 但长期用药对肝脏的保护作用仍不明确^[3]。此外, 目前NAFLD仍没有FDA批准的治疗药物^{[4, 5]}。在化学药治疗效果有限的情况下研究者是否可以另辟蹊径从植物药中寻找治疗T2DM-NAFLD的药物^[6-8]？

毛菊苣是菊科菊苣属植物毛菊苣干燥的地上茎部分, 富含黄酮、生物碱和萜类成分^[9], 具清肝利胆、健胃消食, 利尿消肿的功效^[10]。毛菊苣的相关文献报道主要集中在脂肪肝和糖尿病的治疗上^{[11, 12]}。在治疗肝病方面, 体内外脂质过载条件下, 毛菊苣可有效减少脂质积累保护肝细胞免受损伤和炎症^[13], 并通过下调TNF-α、TGF-β、IL-6和NF-κB等因子减轻肝脏炎症^[14]; 糖尿病方面, 毛菊苣具有体内外抗氧化及抑制α-葡萄糖苷酶和淀粉酶的作用^[15], 并通过多种通路降低血浆胰岛素及肝脏游离脂肪酸水平(FFA)^[16]。本课题组前期研究结果表明, 毛菊苣乙酸乙酯部位可通过NF-κB信号通路发挥降糖作用^[17]。T2DM和NAFLD同为代谢性疾病, T2DM和NAFLD之间关联有多少？毛菊苣可能的靶点和T2DM-NAFLD之间有何关系？毛菊苣有没有可能在治疗糖尿病的同时保护肝脏？这些是本工作探讨的问题。

系统药理学整合了网络药理学和系统生物学, 可揭示化合物-靶点-疾病-通路之间的内在复杂关系, 为揭示疾病的发病机制提供了系统的方法^[18-21]。Liu等^[22]通过系统药理学剖析中药复方藏红花配方以揭示心血管疾病的多尺度治疗策略。Wang等^[23]通过系统药理学对枳术丸抗功能性消化不良进行机制探索, 并进一步对枳实白术的协同作用原因进行阐释。系统药理学不光强调中药活性物质组的早期筛选, 同时也强调药物不同组合对机体系统的综合效应^[24], 适合探究中药对复杂的疾病及其并发症作用的活性成分和作用机制。

本工作首先通过动物实验对毛菊苣治疗T2DM-NAFLD的药效进行探究, 并尝试利用系统药理学分析其活性成分, 预测了毛菊苣对T2DM-NAFLD的作用靶点、通路和疾病构成。本工作的思路见图 1。

材料与方法

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仪器、试剂与动物 毛菊苣茎购于新疆麦迪森有限公司饮片厂, 经石河子大学药学院韩博教授鉴定为菊科菊苣属毛菊苣茎(Cichorium glandulosum Boiss.et Huet), 存放于新疆植物药资源利用教育部重点实验室标本室。

链脲佐菌素(STZ, 编号: S0130-1G)购买于Sigma-Aldrich公司, ELISA试剂盒胰岛素、FFA购买于上海酶联生物科技有限公司, 葡萄糖粉剂购于康美保宁(四川)制药有限公司(批号: 140104), 罗格列酮原料药购于济南一通中科化工有限公司(批号: 20140304), 无水乙醇购于天津富宇精细化工有限公司。

日立HITACHI 7080全自动生化分析仪购于日本日立公司, 活力型血糖试纸及血糖仪购于罗氏血糖健康医护公司, Sunrise A-5082酶标仪购于帝肯(上海)贸易有限公司。

雄性SD大鼠60只, 体量180~220 g, 清洁级, 购自新疆医科大学实验动物中心, 动物合格证号: SCXK (新) 2011-0001。12 h明暗周期、湿度(50%~60%)下, 自由获取食物和水。实验前适应性喂养7天。所有操作流程经石河子大学医学院第一附属医院医学伦理委员会批准并依照《实验动物饲养管理和使用指南》开展实验。

毛菊苣提取物制备 毛菊苣茎2 kg以75%乙醇加热(m/v, 1/10)回流3次, 过滤, 合并滤液得到毛菊苣提取物, 45 ℃减压浓缩除去溶剂得到毛菊苣提取物。毛菊苣提取物100 mg相当于生药433 mg。其中含有预测成分18个, 占总预测成分数量的62.1%。分别为: baicalin、calycosin、isorhamnetin、kaempferol、quercetin、quercetin-3-O-galactoside、5, 8, 3', 4'-tetrahydroxy-7-methoxyflavone、isorhamnetin-3-O-β-D-glucoside、8-O-methylsenecioylaustricin、lactucin、lactupicrin、11β, 13-dihydrolactucin、taraxerone、β-sitosterol、8-O-senecioylaustricin、1, 3-dicaffeoylquinic acid、3, 4-dicaffeoylquinic acid和3, 5-dicaffeoylquinic acid。

造模与给药 将实验大鼠随机分为对照组(NC组) 10只, 实验组40只。对照组给予普通饲料喂养, 实验组高脂饲料喂养。10周后, 实验组大鼠一次性腹腔注射STZ 30 mg·kg^-1, 对照组大鼠一次性腹腔注射柠檬酸钠缓冲液。72 h后尾静脉空腹血糖≥11.1 mmol·L^-1者造模成功。将造模成功的大鼠随机分成:模型组(DC组)、阳性药组(RSG组, 罗格列酮4 mg·kg^-1·d^-1)、低剂量组(L组, 毛菊苣提取物100 mg·kg^-1·d^-1)、高剂量组(H组, 毛菊苣提取物200 mg·kg^-1·d^-1)。所有大鼠连续灌胃10周, 每周测定大鼠体重和血糖。

灌胃给药第67天, 所有大鼠过夜禁食10 h后, 灌胃2 g·kg^-1葡萄糖, 尾静脉取血分别测0、30、60、90和120 min时血糖值。

第10周末禁食12 h, 戊巴比妥麻醉, 腹主动脉取血, 4 ℃离心得血清, 采血后立即取出大鼠肝脏组织, 样本于-80 ℃冰箱保存。

血清生化指标检测 采用罗氏活力型血糖仪和血糖试纸测定空腹血糖, 采用上海酶联生物科技有限公司生产的FFA和胰岛素试剂盒检测血清中的FFA和胰岛素水平; 采用日立HITACHI 7080全自动生化分析仪检测血清中的血脂(TC、TG、HDL-C、LDL-C)水平和肝功能(AST、ALT)水平。

肝脏HE染色 将福尔马林固定好的肝脏右叶组织, 常规脱水, 石蜡包埋, 组织切片机连续切成2 µm厚的切片, HE染色, 光学显微镜下观察组织学变化。

构建毛菊苣化合物库 通过文献挖掘毛菊苣所含化合物, 然后通过PubChem、CHEMBL和Chemspider等数据库下载相应化合物的结构^[25]。本研究中, 含有糖基的40个化合物基于糖苷酶水解反应去糖基化, 所以加入它们相应的糖苷配基化学物质到毛菊苣的化合物库进一步研究, 所有去糖基化合物以-qt标记。

ADME筛选 利用口服生物利用度(OB)和类药性(DL)两种ADME模型寻找毛菊苣的候选化合物。OB通过OBioavail 1.1计算得到, DL通过以下公式计算得到:

(1)$F\left( {a, b} \right) = \frac{{ab}}{{{{\left| a \right|}^2} + {{\left| b \right|}^2} - ab}}$

a代表毛菊苣化合物的分子描述符, b代表FDA中所有批准药物的平均相似性指数^[26]。将这些筛选模型的阈值设为OB≥30%、DL≥0.18, 若化合物符合上述标准, 或OB或DL不符合上述标准但含量较大且有明确药理作用则为候选化合物。

靶点预测 首先, 从3个分子靶向预测模型中获得了活性成分的生物学靶标, 这3个预测模型包括相似性综合方法SEA (http://sea.bkslab.org/)、STITCH (http://stitch.embl.de/)以及化学成分综合模型。其次, 将活性化合物输入草药成分目标数据库(HIT数据库, http://lifecenter.sgst.cn/hit/)、治疗靶点数据库(TTD, http://bidd.nus.edu.sg/group/ttd/)和DrugBank获得文献支持的化合物-靶点相互作用, 最后将上述两步获得的植物成分的靶点信息发送到TTD、PharmGKB (http://www.pharmgkb.org)、京都百科全书基因组数据库(KEGG, http://www.genome.jp/kegg/)和毒物基因组比较数据库(CTD, http://ctdbase.org/)以发现靶点相关的疾病。根据靶点相关疾病以及这些疾病的组织分布, 与动脉血管系统、肝病以及代谢相关的靶点均得以保留, 其他的被排除。

网络构建 为解析毛菊苣的潜在分子机制, 本研究构建了化合物-靶点(C-T)网络、化合物-靶点-疾病(C-T-D)网络、化合物-靶点-通路(C-T-P)网络。所有可视化网络图由Cytoscape 3.5.1构建^[27]。

分子对接验证 本研究采用分子对接技术对系统药理学预测部分靶点进行验证。从RCSB PDB数据库(http://www.rcsb.org/)中下载获得靶蛋白结构, 采用autodock vina软件对配体和受体进行对接^[28], 记录连接位点并计算亲和能, 采用PyMol 1.5软件作图。

数据统计统计学检验采用SPSS 17.0统计软件进行分析, 数据以x±s表示, 各组间差异采用单因素方差分析, 两两比较采用ANOVA检验, P < 0.05为差异有统计学意义。

结果与讨论

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1 毛菊苣对T2DM-NAFLD大鼠的治疗效果

1.1 一般状态观察

对照组大鼠精神状态良好, 毛色有光泽, 饮食饮水及尿量正常, 体重呈增加趋势; 而模型组大鼠精神萎靡, 毛色泛黄, 出现“三多一少”症状; 毛菊苣给药组大鼠也出现模型组大鼠的症状, 但症状较轻。

1.2 对大鼠血液生化指标的影响

大鼠实验流程见图 2A。模型组大鼠的血糖、胰岛素以及FFA水平较对照组均显著升高, 而给予毛菊苣提取物后, 其指标相应降低, 其中血糖(图 2B)和胰岛素(图 2C)水平有显著差异(P < 0.001);而毛菊苣提取物与模型组相比, 其FFA变化无显著差异(图 2D)。

给药10周后大鼠血清生化指标见表 1。模型组大鼠的TC、TG、LDL-C水平较对照组均显著升高(P < 0.005、P < 0.05)而HDL-C水平显著降低(P < 0.005)。与模型组大鼠相比, 毛菊苣提取物给药组可以明显降低T2DM-NAFLD大鼠的TC、TG、LDL-C水平, 其中TG和LDL-C水平显著降低(P < 0.01、P < 0.001), HDL-C水平提高(P < 0.001)。结果表明, 毛菊苣可降低TC、TG、LDL-C、增加HDL-C, 起到降血脂的功效。

模型组AST、ALT水平较对照组均显著升高(P < 0.01、P < 0.001), 给予毛菊苣提取物后, 高剂量组AST、ALT水平显著降低(P < 0.05、P < 0.01)。结果表明毛菊苣提取物可减轻肝脏损伤。

1.3 对大鼠血糖及糖耐量的影响

大鼠禁食的OGTT实验结果见图 3。口服给予葡萄糖(2 g·kg^-1)后大鼠的血糖水平在30 min内提高, 并在接下来的90 min内停留在高血糖水平, 120 min时血糖几乎降到初始水平。在口服给予葡萄糖之后, 毛菊苣提取物治疗大鼠的血糖上升趋势得到抑制。以120 min内血糖的曲线下面积(AUC)表示OGTT的结果, 模型组的血糖AUC较对照组显著升高, 差异显著(P < 0.05)。与模型组相比, 毛菊苣给药组可显著降低血糖AUC (P < 0.05)。说明毛菊苣给药组大鼠对葡萄糖耐受性较强, 且降糖作用显著。

1.4 肝脏组织形态学变化

实验大鼠的肝脏组织形态学变化见图 4。对照组大鼠肝细胞形态正常, 排列有序。模型组大鼠肝脏有严重的肝细胞损伤, 肝脏脂肪变形, 肝细胞体积膨大, 细胞索排列紊乱。而与对照组大鼠相比, 毛菊苣给药组大鼠肝脏中未发现明显的组织病理学异常。上述结果表明, 毛菊苣提取物可通过缓解肝细胞排列紊乱、减少肝脏脂质沉积等起到缓解肝脏损伤的作用。

2 系统药理学预测机制

2.1 毛菊苣的活性成分

通过文献挖掘得到了毛菊苣中的174个候选成分。对包括水解去糖基产物在内的214个成分以OB≥30%、DL≥0.18为指标筛选活性成分, 若化合物符合上述标准, 或OB或DL不符合上述标准但含量较大且有明确药理作用则为活性化合物。共得到29个活性成分, 包括10个黄酮类、11个萜类、3个苯丙素类、2个有机酸类和3个生物碱类。所有成分的详细信息见表 2。

2.2 靶点预测及通路和疾病信息收集

首先, 引入SEA、STITCH和化学基因组学模型在内的预测模型综合计算方法获得活性成分的生物学靶点; 其次, 系统挖掘HIT、TTD和DrugBank数据库获得活性成分的靶点, 取上述两步所得靶点的并集, 共鉴定得到了毛菊苣中29个活性成分的198个靶点。通过KEGG数据库收集靶点的117个与T2DM或NAFLD相关通路。通过CTD、KEGG、PharmGKB和TTD等数据库收集得到81个与T2DM或NAFLD相关的疾病。

2.3 C-T网络构建

毛菊苣的C-T网络如图 5所示, 包括29个化合物和198个靶点的547个相互作用。29个活性成分degree的平均值为18.9。degree值最高的前10个化合物分别为槲皮素(degree=100)、山柰酚(degree=41)、胡萝卜苷(degree=32)、豆甾醇(degree=28)、异鼠李素(degree=26)、玉米核黄素-qt (degree=24)、蒲公英甾醇(degree=24)、β-谷甾醇(degree=24)、毛蕊异黄酮(degree=21)、5, 8, 3', 4'-四羟基-7-甲氧基黄酮(degree=20)。另一方面, 很多靶点被不同数量的化合物靶向, 如PIK3R1、GLB1、GLUT2、G6PD等。毛菊苣的靶点信息分析结果如图 6所示, 对所有相关靶点的生化类型进行分析, 靶点主要分为酶(58.64%)、膜受体(19.37%)、转录因子(5.24%)、转运体(5.24%)等(图 6A)。在112个酶中, 36个酶是氧化还原酶, 36个酶是转移酶、28个水解酶和12个裂合酶(图 6B)。在靶点对应的疾病方面, 主要与营养和代谢性疾病、消化系统疾病和心血管疾病有关(图 6C)。

2.4 C-T-P和C-T-D网络分析

如图 7所示, C-T-P网络中包含了344个节点(29个化合物, 198个靶点, 117个通路)和1 388个相互作用。106个靶点与T2DM有关, 88个靶点与NAFLD有关, 其中T2DM和NAFLD共同的靶点有56个, 这些共同靶点主要和胰岛素抵抗和炎症有关。Degree值最高的6个通路依次为代谢通路(degree=55)、钙信号通路(degree=31)、cAMP通路(degree=29)、cGMP-PKG通路(degree=22)、MAPK通路(degree=20)和PI3K/Akt通路(degree=19)。此外, 与T2DM-NAFLD均相关的通路如胰岛素通路、胰岛素抵抗、NF-κB通路中毛菊苣分别影响15、12、12个靶点。代谢通路包含一系列的下游通路, 如能量代谢、糖水化合物和脂代谢等, 在代谢性疾病发挥着重要作用。NF-κB通路是免疫反应的调节者之一, 在肥胖相关的代谢性疾病中具有关键作用^{[29, 30]}。MAPK通路可以激活调节糖转运体的表达^[31]。PI3K/Akt通路可以调节T2DM大鼠肝糖元合成^[32]。抑制cAMP通路可减缓糖尿病心脏微血管损伤进而减少糖尿病并发症的发生^[33]。上述结果表明, 毛菊苣可能通过调节代谢通路、MAPK、PI3K/Akt等通路发挥治疗T2DM-NAFLD作用。

C-T-D网络图如图 8所示, 包含308个节点(29个化合物, 198个靶点, 81个疾病)和933个相互作用。degree值最高的前6个疾病依次为高血压、肝硬化、T2DM、糖尿病、炎症和肥胖, 依次为29、27、27、19、19、16。106个靶点与T2DM有关, 88个靶点与NAFLD有关, 值得注意的是, 56个靶点为T2DM和NAFLD共有, 主要涉及胰岛素抵抗和炎症。PIK3R1具有最高的degree值, 随后依次为PTGS2、G6PD、HTR2A、INSR, 其中PIK3R1和INSR与糖尿病及糖尿病相关疾病(包括T2DM、胰岛素抵抗和NAFLD)的关系最密切, 而PTGS2、G6PD、HTR2A与糖尿病并发症有关。NAFLD相关的靶点包括INSR、IKBKB、PIK3R1、GSK3B、TNFRSF1A都与T2DM有关, 表明毛菊苣可能通过上述靶点对T2DM-NAFLD起治疗作用。Degree最高的前10个化合物(异鼠李素、槲皮素、β-谷甾醇、胡萝卜苷、豆甾醇、蒲公英甾醇、毛蕊异黄酮、山柰酚、玉米核黄素-qt和5, 8, 3', 4'-四羟基-7-甲氧基黄酮)都与NAFLD、炎症和糖尿病包括T2DM直接相关。

2.5 分子对接验证

从系统药理学预测的靶点中选取PIK3R1、PTGS2、G6PD、HTR2A、INSR 5个关键靶蛋白, 对其配体进行分子对接并计算亲和力。亲和力最高的5个靶蛋白及其配体的分子对接图如图 9所示, 这5组靶蛋白和配体组合分别为PTGS2和M05、INSR和M09、PIK3R1和M06、HTR2A和M24、G6PD和M22。5个靶蛋白及其在系统药理学预测的活性化合物之间的亲和力及连接位点见表 3。结果表明, 这5个靶蛋白与所对应的配体之间均具有良好的亲和性。

目前系统药理学主要用于一味或多味中药对一个疾病的作用机制研究, 如Yue等^[34]通过系统药理学明确了当归红花片对血瘀症的作用机制。本课题组^[35]通过系统药理学研究了没食子抗溃疡性结肠炎的物质基础和作用机制。但研究者往往忽略了系统药理学(或网络药理学)作为一件强大的科学工具可用于适应证或复杂适应证的分析上。用于复杂症候分析的工作并不多见, 如清华大学李梢课题组^[36]通过网络药理学工具对中医的复杂症候“寒”和“热”症候和药性进行了分析, 相对清晰地勾勒了药物-靶点-疾病的轮廓。类似的, 本工作分析了一种植物药对T2DM和NAFLD两种疾病之间的作用靶点以及两种疾病T2DM和NAFLD之间的关系, 为科学扩展和梳理药物的适应证提供了有益参考。

一个靶点对应的疾病可能会涉及不同系统的疾病, 而草药中多个化合物对应的靶点信息复杂, 相关的疾病多种多样。因为本工作所研究疾病为T2DM和NAFLD, 因此与这两种疾病相关的疾病被保留下来, 如T2DM涉及的疾病包括各种大小血管并发症, 以及相关的代谢性疾病和心血管疾病; NAFLD涉及的肝硬化、肝纤维化等疾病也得以保留。

结论

收起

动物实验表明, 毛菊苣可以显著改善T2DM-NAFLD大鼠的血糖血脂水平, 改善糖耐量并减少AST、ALT, 改善肝脏细胞排列, 减少肝脏脂质沉积的作用。系统药理学结果表明, 毛菊苣可能通过调节代谢通路、钙信号通路、PI3K/Akt、cAMP、MAPK等通路治疗T2DM-NAFLD, 共筛选和预测得到了29个活性化合物、198个靶点、117个通路和81个疾病。涉及T2DM的靶点有106个, 涉及NAFLD的靶点有88个, T2DM和NAFLD共有的靶点有56个, 主要与胰岛素抵抗和炎症有关, 198个靶点主要参与了代谢通路、钙信号通路、PI3K/Akt信号通路、cAMP通路、MAPK通路等。本研究为毛菊苣治疗2型糖尿病伴随非酒精性脂肪肝提供了理论和实验基础。

基金

收起

国家自然科学基金资助项目(81760756)
石河子大学杰出青年科技人才培育计划(2015ZRKXJQ08)

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2019年第54卷第11期

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文章信息

doi: 10.16438/j.0513-4870.2019-0114

接收时间：2019-02-13
首发时间：2026-01-26
出版时间：2019-11-12

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收稿日期：2019-02-13
修回日期：2019-04-24

基金

国家自然科学基金资助项目(81760756)

石河子大学杰出青年科技人才培育计划(2015ZRKXJQ08)

作者信息

1.石河子大学药学院, 新疆石河子 832002

2.北京科兴生物制品有限公司, 北京 100085

通讯作者:

*韩博, Tel: 86-993-2613049, E-mail: hanbodexinxiang@163.com

参考文献

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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2019-0114

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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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Group	Body weight/g	TC/mmol·L^-1	TG/mmol·L^-1	HDL-C/mmol·L^-1	LDL-C/mmol·L^-1	AST/U·L^-1	ALT/U·L^-1
NC	471.8 ± 16.90	1.150 ± 0.092 74	0.150 0 ± 0.047 61	0.935 0 ± 0.069 52	0.410 0 ± 0.049 67	84.00 ± 7.79	29.75 ± 2.062
DC	322.0 ± 12.83^###	1.363 ± 0.145 70^#	0.367 5 ± 0.020 62^###	0.437 5 ± 0.066 52^###	0.860 0 ± 0.075 28^###	110.8 ± 8.88^##	62.00 ± 8.602^###
RSG	383.0 ± 7.70^***	1.185 ± 0.023 80	0.215 0 ± 0.031 09^***	0.812 5 ± 0.091 06^***	0.445 0 ± 0.031 09^***	85.75 ± 7.50^**	35.25 ± 5.909^***
L	350.3 ± 21.96	1.285 ± 0.096 78	0.215 0 ± 0.031 09^**	0.702 5 ± 0.066 02^***	0.622 5 ± 0.087 32^***	93.00 ± 14.72	45.50 ± 8.347^*
H	365.8 ± 24.60^**	1.245 ± 0.068 07	0.255 0 ± 0.041 23^***	0.797 5 ± 0.086 55^***	0.515 0 ± 0.064 55^***	91.00 ± 11.92^*	40.00 ± 10.200^**

Group

Body weight/g

TC/mmol·L^-1

TG/mmol·L^-1

HDL-C/mmol·L^-1

LDL-C/mmol·L^-1

AST/U·L^-1

ALT/U·L^-1

471.8 ± 16.90

1.150 ± 0.092 74

0.150 0 ± 0.047 61

0.935 0 ± 0.069 52

0.410 0 ± 0.049 67

84.00 ± 7.79

29.75 ± 2.062

322.0 ± 12.83^###

1.363 ± 0.145 70^#

0.367 5 ± 0.020 62^###

0.437 5 ± 0.066 52^###

0.860 0 ± 0.075 28^###

110.8 ± 8.88^##

62.00 ± 8.602^###

RSG

383.0 ± 7.70^***

1.185 ± 0.023 80

0.215 0 ± 0.031 09^***

0.812 5 ± 0.091 06^***

0.445 0 ± 0.031 09^***

85.75 ± 7.50^**

35.25 ± 5.909^***

350.3 ± 21.96

1.285 ± 0.096 78

0.215 0 ± 0.031 09^**

0.702 5 ± 0.066 02^***

0.622 5 ± 0.087 32^***

93.00 ± 14.72

45.50 ± 8.347^*

365.8 ± 24.60^**

1.245 ± 0.068 07

0.255 0 ± 0.041 23^***

0.797 5 ± 0.086 55^***

0.515 0 ± 0.064 55^***

91.00 ± 11.92^*

40.00 ± 10.200^**

No.	Name	OB	DL	Compound type
M01	Baicalin	41.24	0.24	Flavonoids
M02	Calycosin	47.73	0.24
M03	Isorhamnetin	52.29	0.73
M04	Kaempferol	62.13	0.24
M05	Quercetin	45.06	0.28
M06	Quercetin-3-O-galactoside	68.28	0.19
M07	5, 8, 3', 4'-Tetrahydroxy-7-methoxyflavone	49.91	0.30
M08	5, 8, 4'-Trihydroxy-7, 3'-dimethoxyflavone	63.49	0.34
M09	Baicalin methyl ester	39.69	0.79
M10	Isorhamnetin-3-O-β-D-glucoside	60.00	0.74
M11	8-O-Methylsenecioylaustricin	64.08	0.41	Terpenoids
M12	Daucosterol-qt	36.91	0.75
M13	Inulicin	30.60	0.22
M14	Lactucin	29.81	0.22
M15	Lactupicrin	18.93	0.71
M16	Stigmasterol	64.91	0.75
M17	11β, 13-Dihydrolactucin	39.56	0.22
M18	Taraxerone	64.59	0.19
M19	β-Sitosterol	36.91	0.75
M20	8-O-Senecioylaustricin	104.45	0.62
M21	Lupeol acetate	52.29	0.73
M22	1, 3-Dicaffeoylquinic acid	52.22	0.63	Phenylpropanoid
M23	3, 4-Dicaffeoylquinic acid	71.29	0.69
M24	3, 5-Dicaffeoylquinic acid	50.06	0.69
M25	4, 4'-Dimethyl-1, 7-heptane diacid	41.83	0.64	Organic acids
M26	Carnaubic acid	41.83	0.64
M27	2-Furanmethanol-(5'→11)-1, 3-cyclopentadiene-[5, 4-c]-1H-cinnoline	74.20	0.28	Alkaloids
M28	Corn riboflavin	56.56	0.76
M28-qt	Corn riboflavin-qt	30.81	0.19

No.

Name

Compound type

Chemical structure

M01

Baicalin

41.24

0.24

Flavonoids

M02

Calycosin

47.73

0.24

M03

Isorhamnetin

52.29

0.73

M04

Kaempferol

62.13

0.24

M05

Quercetin

45.06

0.28

M06

Quercetin-3-O-galactoside

68.28

0.19

M07

5, 8, 3', 4'-Tetrahydroxy-7-methoxyflavone

49.91

0.30

M08

5, 8, 4'-Trihydroxy-7, 3'-dimethoxyflavone

63.49

0.34

M09

Baicalin methyl ester

39.69

0.79

M10

Isorhamnetin-3-O-β-D-glucoside

60.00

0.74

M11

8-O-Methylsenecioylaustricin

64.08

0.41

Terpenoids

M12

Daucosterol-qt

36.91

0.75

M13

Inulicin

30.60

0.22

M14

Lactucin

29.81

0.22

M15

Lactupicrin

18.93

0.71

M16

Stigmasterol

64.91

0.75

M17

11β, 13-Dihydrolactucin

39.56

0.22

M18

Taraxerone

64.59

0.19

M19

β-Sitosterol

36.91

0.75

M20

8-O-Senecioylaustricin

104.45

0.62

M21

Lupeol acetate

52.29

0.73

M22

1, 3-Dicaffeoylquinic acid

52.22

0.63

Phenylpropanoid

M23

3, 4-Dicaffeoylquinic acid

71.29

0.69

M24

3, 5-Dicaffeoylquinic acid

50.06

0.69

M25

4, 4'-Dimethyl-1, 7-heptane diacid

41.83

0.64

Organic acids

M26

Carnaubic acid

41.83

0.64

M27

2-Furanmethanol-(5'→11)-1, 3-cyclopentadiene-[5, 4-c]-1H-cinnoline

74.20

0.28

Alkaloids

M28

Corn riboflavin

56.56

0.76

M28-qt

Corn riboflavin-qt

30.81

0.19

Protein	PDB ID	Compound	Affinity/kcal·mol ^-1	Amino acid
PTGS2	4PH9	M05	-8.4	TYR-356, PHE-519, TYR-386, HIS-90
INSR	5E1S	M02	-7.4	MET 1079, LEU-1002
INSR	5E1S	M03	-8.2	MET-1079
INSR	5E1S	M04	-7.6	LEU-1002
INSR	5E1S	M05	-7.6	LEU-1002, MET-1079, ASP-1150
INSR	5E1S	M06	-8.5	ASP-1150, GLY-1003
INSR	5E1S	M08	-7.9	ASP-1150
INSR	5E1S	M09	-8.9	ASP-1150, MET-1079
PIK3R1	5XGH	M02	-7.2	VAL-851, SER-854, GLU-849
PIK3R1	5XGH	M03	-7.7	TYR-836, ASN-170
PIK3R1	5XGH	M04	-7.7	LEU-814
PIK3R1	5XGH	M05	-7.9	TYR-836, ASP-626
PIK3R1	5XGH	M06	-8.7	CYS-838, HIS-670, GLN-815, GLN-630, ILE-633, ARG-818, ASN-170
PIK3R1	5XGH	M07	-8.2	TYR-836, VAL-851
PIK3R1	5XGH	M08	-8.1	TYR-836, ASP-933, VAL-851
PIK3R1	5XGH	M09	-8.4	CYS-838, TYR-836
PIK3R1	5XGH	M12	-8.3	-
PIK3R1	5XGH	M13	-7.0	-
PIK3R1	5XGH	M15	-8.8	CYS-838
PIK3R1	5XGH	M17	-7.1	PRO-835, ARG-818, GLN-630, CYS-838
PIK3R1	5XGH	M19	-7.9	GLU-849
PIK3R1	5XGH	M20	-8.2	ARG-818
PIK3R1	5XGH	M21	-9.0	-
PIK3R1	5XGH	M22	-8.5	TYR-836, CYS-838, ASN-756, ASN-170
PIK3R1	5XGH	M27	-8.6	TYR-836, VAL-851
HTR2A	6A94	M01	-7.6	LEU-229, CYS-227
HTR2A	6A94	M03	-9.0	SER-239
HTR2A	6A94	M06	-7.5	TYR-370, LEU-229, VAL-156, THR-160
HTR2A	6A94	M08	-8.2	ASN-343, TYR-370
HTR2A	6A94	M09	-6.8	ASN-363, TYR-139
HTR2A	6A94	M10	-6.1	ASN-363, ASP-356
HTR2A	6A94	M11	-8.3	ASN-343, SER-239
HTR2A	6A94	M16	-8.0	-
HTR2A	6A94	M23	-9.0	SER-242, THR-160, ILE-206
HTR2A	6A94	M24	-10.9	LEU-229, TRP-367, SER-131, THR-160
HTR2A	6A94	M25	-5.7	VAL-235
G6PD	6E08	M07	-7.0	TRP-509, ASP-421
G6PD	6E08	M12	-7.8	-
G6PD	6E08	M13	-5.7	LYS-366, ARG-370
G6PD	6E08	M17	-6.3	ARG-487
G6PD	6E08	M19	-7.7	-
G6PD	6E08	M21	-7.4	-
G6PD	6E08	M22	-9.3	ARG-370, LYS-366, THR-236
G6PD	6E08	M28	-6.6	ASP-421, ARG-370, ARG-487

Protein

PDB ID

Compound

Affinity/kcal·mol ^-1

Amino acid

PTGS2

4PH9

M05

-8.4

TYR-356, PHE-519, TYR-386, HIS-90

INSR

5E1S

M02

-7.4

MET 1079, LEU-1002

INSR

5E1S

M03

-8.2

MET-1079

INSR

5E1S

M04

-7.6

LEU-1002

INSR

5E1S

M05

-7.6

LEU-1002, MET-1079, ASP-1150

INSR

5E1S

M06

-8.5

ASP-1150, GLY-1003

INSR

5E1S

M08

-7.9

ASP-1150

INSR

5E1S

M09

-8.9

ASP-1150, MET-1079

PIK3R1

5XGH

M02

-7.2

VAL-851, SER-854, GLU-849

PIK3R1

5XGH

M03

-7.7

TYR-836, ASN-170

PIK3R1

5XGH

M04

-7.7

LEU-814

PIK3R1

5XGH

M05

-7.9

TYR-836, ASP-626

PIK3R1

5XGH

M06

-8.7

CYS-838, HIS-670, GLN-815, GLN-630, ILE-633, ARG-818, ASN-170

PIK3R1

5XGH

M07

-8.2

TYR-836, VAL-851

PIK3R1

5XGH

M08

-8.1

TYR-836, ASP-933, VAL-851

PIK3R1

5XGH

M09

-8.4

CYS-838, TYR-836

PIK3R1

5XGH

M12

-8.3

PIK3R1

5XGH

M13

-7.0

PIK3R1

5XGH

M15

-8.8

CYS-838

PIK3R1

5XGH

M17

-7.1

PRO-835, ARG-818, GLN-630, CYS-838

PIK3R1

5XGH

M19

-7.9

GLU-849

PIK3R1

5XGH

M20

-8.2

ARG-818

PIK3R1

5XGH

M21

-9.0

PIK3R1

5XGH

M22

-8.5

TYR-836, CYS-838, ASN-756, ASN-170

PIK3R1

5XGH

M27

-8.6

TYR-836, VAL-851

HTR2A

6A94

M01

-7.6

LEU-229, CYS-227

HTR2A

6A94

M03

-9.0

SER-239

HTR2A

6A94

M06

-7.5

TYR-370, LEU-229, VAL-156, THR-160

HTR2A

6A94

M08

-8.2

ASN-343, TYR-370

HTR2A

6A94

M09

-6.8

ASN-363, TYR-139

HTR2A

6A94

M10

-6.1

ASN-363, ASP-356

HTR2A

6A94

M11

-8.3

ASN-343, SER-239

HTR2A

6A94

M16

-8.0

HTR2A

6A94

M23

-9.0

SER-242, THR-160, ILE-206

HTR2A

6A94

M24

-10.9

LEU-229, TRP-367, SER-131, THR-160

HTR2A

6A94

M25

-5.7

VAL-235

G6PD

6E08

M07

-7.0

TRP-509, ASP-421

G6PD

6E08

M12

-7.8

G6PD

6E08

M13

-5.7

LYS-366, ARG-370

G6PD

6E08

M17

-6.3

ARG-487

G6PD

6E08

M19

-7.7

G6PD

6E08

M21

-7.4

G6PD

6E08

M22

-9.3

ARG-370, LYS-366, THR-236

G6PD

6E08

M28

-6.6

ASP-421, ARG-370, ARG-487