基于分子对接和药效团的磷脂酶PLA2G1B抑制剂的虚拟筛选

王玉婷; 刘霞; 彭媛媛; 王潇婕; 赵琳静

doi:10.12299/jsues.22-0051

基于分子对接和药效团的磷脂酶PLA2G1B抑制剂的虚拟筛选

doi: 10.12299/jsues.22-0051

上海工程技术大学化学化工学院, 上海 201620

基金项目: 国家自然科学基金项目资助 (31701032)

详细信息

作者简介:
王玉婷 (1994−)，女，在读硕士，研究方向为天然药物. E-mail: 194588117@qq.com

通讯作者:
赵琳静 (1979−)，女，副教授，博士，研究方向为天然药物功效基础及作用机制. E-mail: ljzhao@sues.edu.cn

中图分类号: R914
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出版历程
- 收稿日期: 2022-03-08
- 刊出日期: 2022-06-30

Virtual screening of phospholipase PLA2G1B inhibitors based on molecular docking and pharmacophore

School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China

摘要

摘要:
磷脂酶PLA2G1B 与饮食诱导肥胖及相关代谢紊乱密切联系，研究表明一些天然类黄酮化合物对磷脂酶有抑制作用. 采用整合分子对接和药效团策略筛选PLA2G1B靶向小分子抑制剂. 对5种类黄酮化合物与PLA2G1B靶标进行分子模拟对接，分析其相互作用，建立基于配体分子共同特征（HipHop）的药效团模型，应用该模型对ZINC数据库中小分子化合物进行筛选，并对匹配评分良好的化合物进行类药性和药代动力学性质（ADME）预测分析. 结果表明，山柰酚、木犀草素、槲皮素、杨梅素和表没食子儿茶素没食子酸酯与PLA2G1B均能较好结合，结合能为−7.17~−6.17 kJ/mol；所构建的药效团模型含有3个氢键供体和1个氢键受体4个特征元素；通过对ZINC数据库中10 897个小分子的筛选，共得到722个分子，命中率为6.6%. 其中匹配评分>2.5的29个化合物均满足Lipinski规则，大部分化合物的ADME参数良好. 研究结果为PLA2G1B抑制剂设计及先导化合物发现提供了参考数据.
- PLA2G1B抑制剂 /
- 类黄酮 /
- 分子对接 /
- 药效团 /
- 虚拟筛选
Abstract:
Phospholipase PLA2G1B is closely related to diet-induced obesity and related metabolic disorders. Studies have shown that some natural flavonoid compounds can inhibit phospholipase. An integrated molecular docking and pharmacophore strategy was used to screen PLA2G1B-targeted small molecule inhibitors. Molecular docking of five flavonoid compounds with PLA2G1B were possessed, and their interaction patterns were analyzed. A pharmacophore model based on common ligand molecular characteristics (HipHop) was established, which was used to screen small molecular compounds from ZINC database. The drug-likeness and pharmacokinetic properties (ADME) of the compounds with good fit values were predicted. The results show that kaempferol, luteolin, quercetin, myricetin and epigallocatechin gallate can bind PLA2G1B well, with the binding energies of −7.17~−6.17 kJ/mol. The pharmacophore model consisted of three hydrogen bond donors and one hydrogen bond receptor. By screening 10 897 small molecules in ZINC database, a total of 722 molecules with a hit rate of 6.6% were obtained. The 29 compounds with fit values higher than 2.5 are all meeting Lipinski's rule, and most of the compounds have good ADME parameters. These results can provide reference data for the design of PLA2G1B inhibitors and discovery of lead compounds.
- PLA2G1B inhibitor /
- flavonoid /
- molecular docking /
- pharmacophore /
- virtual screening

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图 1 类黄酮化合物与PLA2G1B 靶点的分子对接相互作用模式图

Figure 1. Interaction pattern diagram between PLA2G1B target and flavonoid compounds

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图 2 类黄酮化合物与优选药效团的匹配图

Figure 2. Matching pattern diagrams of flavonoid compounds with preferred pharmacophore

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表 1 分子对接结合自由能和氢键作用结果

Table 1. Results of binding energies and hydrogen bond interactions by molecular docking

化合物名称	结合能/(kJ·mol⁻¹)	氢键作用
山柰酚（Kaempferol）	−7.17	ARG−6、ASN−23、TYR−22、TYR−69
木犀草素（Luteolin）	−6.80	AGR−6、ASN−23、ASP−49
槲皮素（Quercetin）	−6.32	ASP−53和ASN−23
杨梅素（Myricetin）	−6.19	ASN−23、ASP−53、GLY−32
表没食子儿茶素没食子酸酯（Epigallocatechin gallate）	−6.17	ASN−101、CYS−44、THR−47、ASN−50、PHE−94

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表 2 10 个基于分子共同特征的药效团的结果参数

Table 2. Parameters of ten common features of pharmacophore

模型编号	特征元素	评分	最高匹配
01	DDDA	56.532	4
02	DDDA	56.430	4
03	DDAA	56.207	4
04	DDDA	56.017	4
05	DDAA	56.013	4
06	DDDA	55.571	4
07	DDDA	55.571	4
08	DDAA	55.532	4
09	DDAA	55.532	4
10	DDAA	55.532	4

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表 3 基于药效团筛选、类药性及ADME分析得到29个小分子各项得分值

Table 3. Scores of each index of 29 molecules obtained based on pharmacophore screening, drug-likeness and ADME analysis

序号	化合物	匹配评分	Lipinski规则	Veber规则	Absorption	Solubility	BBB	CYP2D6	PPB
1	ZINC001151173718	3.17	Yes	No	3	4	4	False	False
2	ZINC001454282551	3.06	Yes	Yes	3	5	4	False	False
3	ZINC001558022086	3.01	Yes	Yes	1	5	4	False	False
4	ZINC001363316402	2.94	Yes	Yes	2	4	4	False	False
5	ZINC001179227552	2.92	Yes	Yes	1	4	4	False	False
6	ZINC001363491746	2.91	Yes	Yes	0	4	3	False	False
7	ZINC000824680228	2.91	Yes	No	2	4	4	False	False
8	ZINC001294455752	2.83	Yes	Yes	1	5	4	False	False
9	ZINC000825929851	2.82	Yes	No	2	4	4	False	False
10	ZINC001176845653	2.75	Yes	No	3	4	4	False	False
11	ZINC001130958954	2.67	Yes	No	3	5	4	False	False
12	ZINC000347737500	2.66	Yes	Yes	2	5	4	False	False
13	ZINC001411973522	2.66	Yes	Yes	1	5	4	False	False
14	ZINC001442587981	2.65	Yes	Yes	3	5	4	False	False
15	ZINC001434077453	2.62	Yes	Yes	2	5	4	False	False
16	ZINC001362720157	2.62	Yes	Yes	2	5	4	False	False
17	ZINC000824680227	2.61	Yes	No	2	4	4	False	False
18	ZINC001434077450	2.61	Yes	Yes	2	5	4	False	False
19	ZINC001346217825	2.61	Yes	Yes	3	5	4	False	False
20	ZINC001138190537	2.60	Yes	Yes	1	5	4	False	False
21	ZINC000337596865	2.60	Yes	Yes	1	5	4	False	False
22	ZINC001179227551	2.58	Yes	Yes	1	4	4	False	False
23	ZINC001142378276	2.57	Yes	Yes	3	5	4	False	False
24	ZINC001051505747	2.54	Yes	No	3	5	4	False	False
25	ZINC001090398382	2.54	Yes	No	3	4	4	False	False
26	ZINC001592749923	2.54	Yes	No	3	5	4	False	False
27	ZINC000352614243	2.53	Yes	No	3	5	4	False	False
28	ZINC001168946047	2.51	Yes	No	1	5	4	False	False
29	ZINC001133116414	2.51	Yes	No	3	5	4	False	False

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