基于虚拟筛选发现潜在的黄嘌呤氧化酶抑制剂

doi:10.5246/jcps.2023.08.052

中国药学(英文版) ›› 2023, Vol. 32 ›› Issue (8): 626-635.DOI: 10.5246/jcps.2023.08.052

基于虚拟筛选发现潜在的黄嘌呤氧化酶抑制剂

迟骁玮^#, 黎奇^#, 钟毅^#, 龚桐, 衣楚潇, 张亮仁^*(), 刘振明^*()

北京大学医学部药学院天然药物及仿生药物全国重点实验室, 北京 100191

收稿日期:2023-01-23 修回日期:2023-03-22 接受日期:2023-04-05 出版日期:2023-08-31 发布日期:2023-08-31
通讯作者: 张亮仁, 刘振明
作者简介:
+ Tel.: +86-10-82805281, E-mail: zmliu@bjmu.edu.cn
+ E-mail: liangren@bjmu.edu.cn
基金资助:
Beijing Natural Science Foundation (Grant No. 7202088).

Discovery of potential xanthine oxidase inhibitors based on virtual screening

Xiaowei Chi^#, Qi Li^#, Yi Zhong^#, Tong Gong, Chuxiao Yi, Liangren Zhang^*(), Zhenming Liu^*()

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2023-01-23 Revised:2023-03-22 Accepted:2023-04-05 Online:2023-08-31 Published:2023-08-31
Contact: Liangren Zhang, Zhenming Liu
About author:
# These authors contributed to the work equally.

摘要/Abstract

摘要：

随着生活水平的不断提高, 痛风的发病率迅速增加, 并且在年轻人中越来越常见。黄嘌呤氧化酶(Xanthine oxidase, XO)是治疗痛风的关键靶点, 因为抑制XO可以有效减少体内尿酸的产生, 缓解痛风症状。在这项研究中, 通过虚拟筛选确定了三种潜在的XO抑制剂, 并使用表面等离子体共振(Surface plasmon resonance, SPR)进行了验证。在这些抑制剂中, Floxuridine在0.35 μM时表现出最强的结合活性, 而阳性药物别嘌醇的结合活性为0.76 μM。通过分子动力学模拟验证了这些化合物与XO的结合模式。值得注意的是, 这三种化合物都已被批准为上市药物, 安全性得到保证, 表明它们有可能成为有效的XO抑制剂。

关键词: 虚拟筛选, 黄嘌呤氧化酶抑制剂, 表面等离子体共振, 药物发现

Abstract:

With the continuous improvement of living standards, the incidence of gout is increasing rapidly, and it is becoming more common among younger individuals. Xanthine oxidase (XO) is a crucial target for treating gout, as inhibiting XO can effectively reduce the production of uric acid in the body and alleviate gout symptoms. In the present study, three potential XO inhibitors were identified through virtual screening and validated using surface plasmon resonance (SPR). Among these inhibitors, floxuridine exhibited the strongest binding activity at 0.35 μM, compared with 0.76 μM for the positive drug allopurinol. Molecular dynamics simulations were conducted to examine the binding pattern of these compounds with XO. It is noteworthy that all three compounds are already approved as marketed drugs and have established safety profiles, indicating their potential as effective XO inhibitors.

Key words: Virtual screening, Xanthine oxidase inhibitors, Surface plasmon resonance, Drug discovery

Supporting: /attached/file/20230903/20230903000355_184.pdf

迟骁玮, 黎奇, 钟毅, 龚桐, 衣楚潇, 张亮仁, 刘振明. 基于虚拟筛选发现潜在的黄嘌呤氧化酶抑制剂[J]. 中国药学(英文版), 2023, 32(8): 626-635.

Xiaowei Chi, Qi Li, Yi Zhong, Tong Gong, Chuxiao Yi, Liangren Zhang, Zhenming Liu. Discovery of potential xanthine oxidase inhibitors based on virtual screening[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(8): 626-635.

图/表 5

Figure 1. Chemical structures of allopurinol, topiroxostat, and febuxostat.

Table 1. Docking and SPR results of 11 compounds selected from virtual screening.

Figure 2. The interaction pattern analysis of the initial docking conformation of floxuridine/sulfasalazine. The solid blue line represents hydrogen bonding interactions, the gray dashed line represents hydrophobic interactions, the light yellow dashed line represents salt bridges, the green dashed line represents π-stacking, and the orange dashed line represents π-cation interactions.

Figure 3. The RMSD with the time of the protein backbone atoms, ligand weight atoms of sulfasalazine, and floxuridine in the MD simulations.

Figure 4. The structural superposition of the initial docking conformation of sulfasalazine/floxuridine and the conformation after MD simulations. The interaction pattern analysis of the conformations after MDs. The solid blue line represents hydrogen bonding interactions, and the gray dashed line represents hydrophobic interactions.

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基于虚拟筛选发现潜在的黄嘌呤氧化酶抑制剂

Discovery of potential xanthine oxidase inhibitors based on virtual screening

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