| 萧耿苗,穆云萍,千爱君,李芳红,赵子建.低心血管疾病风险选择性环氧合酶-2抑制剂的虚拟筛选[J].,2024,(5):807-812 |
| 低心血管疾病风险选择性环氧合酶-2抑制剂的虚拟筛选 |
| Virtual Screening of Selective Cyclooxygenase-2 Inhibitors with Low Cardiovascular Disease Risk |
| 投稿时间：2023-09-18 修订日期：2023-10-13 |
| DOI：10.13241/j.cnki.pmb.2024.05.002 |
| 中文关键词: 虚拟筛选 选择性COX-2抑制剂 TP抑制剂 低心血管疾病风险 |
| 英文关键词: Virtual screening Selective COX-2 inhibitors TP inhibitors Low cardiovascular disease risk |
| 基金项目:国家重点研发计划项目（2018YFA0800603）；广东省"珠江人才计划"项目（2016ZT06Y432）；广东省重点领域研发计划项目（2019B020201015） |
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| 中文摘要: |
| 摘要 目的：寻找具有血栓素A2受体（Thromboxane A2 receptor，TP）抑制作用的选择性环氧合酶-2（Cyclooxygenase-2，COX-2）抑制剂，以期降低其心血管疾病风险。方法：本研究从公开数据库中获取了512种TP抑制剂，通过分子对接、分子动力学模拟和ADMET预测，筛选出化合物TP84。结果：分子对接结果显示，与先前获批的选择性COX-2抑制剂罗非昔布相比，TP84对COX-2的亲和力更高，对环氧合酶-1（Cyclooxygenase-1，COX-1）的亲和力更低；分子动力学模拟进一步表明，模拟过程中TP84与COX-1的结合不稳定，而TP84能稳定结合COX-2，与COX-2的结合自由能是COX-1的3倍；此外，根据ADMET预测，TP84的药物化学、吸收、分布、代谢、排泄和毒性处于类药物候选物的可接受范围内。结论：TP84是一种潜在的低心血管疾病风险选择性COX-2抑制剂。 |
| 英文摘要: |
| ABSTRACT Objective: To find selective Cyclooxygenase-2 (COX-2) inhibitors with thromboxane A2 receptor (TP) inhibition with the aim of reducing their cardiovascular disease risk. Methods: In this study, a total of 512 TP inhibitors were obtained from public databases. Through molecular docking, molecular dynamics simulation, and ADMET prediction, a compound named TP84 was identified. Results: The molecular docking results demonstrate that TP84 exhibits higher affinity for COX-2 and lower affinity for Cyclooxygenase-1 (COX-1) compared with rofecoxib, a previously approved selective COX-2 inhibitor. Furthermore, molecular dynamics simulation reveals that TP84 binds unstably to COX-1 during simulations, whereas TP84 can bind COX-2 stably. The binding free energy of TP84 to COX-2 was three times higher than that of COX-1. Furthermore, the medicinal chemistry, absorption, distribution, metabolism, excretion and toxicological properties of TP84 are predicted by ADMET to be within the acceptable range for drug-like candidates. Conclusion: TP84 is a potential selective COX-2 inhibitor drug with low cardiovascular disease risk. |
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