{"title":"AILDE 计算机辅助发现以环氧化酶-2 为靶点的新型布洛芬香豆素抗肿瘤先导化合物","authors":"Fengxu Wu, Tianshuai Wang, Xiaoyu Tang, Sirui Dong, Lun Luo, Chao Luo, Junkai Ma, Yanggen Hu","doi":"10.1021/acsomega.4c06596","DOIUrl":null,"url":null,"abstract":"Starting from three ibuprofen–coumarin hit compounds, we designed 18 derivative compounds targeting cyclooxygenase-2 (COX-2) by introducing different substituents onto them by using the computational auto in silico ligand directing evolution (AILDE) method. After synthesizing and testing the activity, we found that 6 representative compounds have micromolar enzyme inhibitory activity against COX-2. Additionally, 16 compounds have shown certain inhibitory activity in cervical cancer cells. Among these compounds, <b>6c</b> (IC<sub>50</sub> = 0.606 μM, HeLa) and <b>7g</b> (IC<sub>50</sub> = 0.783 μM, HeLa) have exhibited excellent activity, which is approximately 10 times better than the commercial drug gefitinib. According to molecular simulation results, the halogen atoms of <b>6c</b> and <b>7g</b> on the coumarin ring can form halogen bonds with COX-2, which significantly improves their activity compared to their hit compounds <b>6a</b> and <b>7a</b>. However, the key interactions were lost in binding with COX-1. The calculation results revealed that the two compounds are selective COX-2 inhibitors, with potential selectivity indexes of 6-fold and 5-fold, respectively. The cell-based activity of compounds <b>6c</b> and <b>7g</b> toward HEK293 cells demonstrates that our compounds possess an acceptable safety toward normal cells. The results indicate that <b>6c</b> and <b>7g</b> can serve as potential lead compounds for further lucubrate.","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"AILDE Computer-Aided Discovery of Novel Ibuprofen–Coumarin Antitumor Lead Compounds Targeting Cyclooxygenase-2\",\"authors\":\"Fengxu Wu, Tianshuai Wang, Xiaoyu Tang, Sirui Dong, Lun Luo, Chao Luo, Junkai Ma, Yanggen Hu\",\"doi\":\"10.1021/acsomega.4c06596\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Starting from three ibuprofen–coumarin hit compounds, we designed 18 derivative compounds targeting cyclooxygenase-2 (COX-2) by introducing different substituents onto them by using the computational auto in silico ligand directing evolution (AILDE) method. After synthesizing and testing the activity, we found that 6 representative compounds have micromolar enzyme inhibitory activity against COX-2. Additionally, 16 compounds have shown certain inhibitory activity in cervical cancer cells. Among these compounds, <b>6c</b> (IC<sub>50</sub> = 0.606 μM, HeLa) and <b>7g</b> (IC<sub>50</sub> = 0.783 μM, HeLa) have exhibited excellent activity, which is approximately 10 times better than the commercial drug gefitinib. According to molecular simulation results, the halogen atoms of <b>6c</b> and <b>7g</b> on the coumarin ring can form halogen bonds with COX-2, which significantly improves their activity compared to their hit compounds <b>6a</b> and <b>7a</b>. However, the key interactions were lost in binding with COX-1. The calculation results revealed that the two compounds are selective COX-2 inhibitors, with potential selectivity indexes of 6-fold and 5-fold, respectively. The cell-based activity of compounds <b>6c</b> and <b>7g</b> toward HEK293 cells demonstrates that our compounds possess an acceptable safety toward normal cells. The results indicate that <b>6c</b> and <b>7g</b> can serve as potential lead compounds for further lucubrate.\",\"PeriodicalId\":22,\"journal\":{\"name\":\"ACS Omega\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Omega\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/acsomega.4c06596\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Omega","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acsomega.4c06596","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
AILDE Computer-Aided Discovery of Novel Ibuprofen–Coumarin Antitumor Lead Compounds Targeting Cyclooxygenase-2
Starting from three ibuprofen–coumarin hit compounds, we designed 18 derivative compounds targeting cyclooxygenase-2 (COX-2) by introducing different substituents onto them by using the computational auto in silico ligand directing evolution (AILDE) method. After synthesizing and testing the activity, we found that 6 representative compounds have micromolar enzyme inhibitory activity against COX-2. Additionally, 16 compounds have shown certain inhibitory activity in cervical cancer cells. Among these compounds, 6c (IC50 = 0.606 μM, HeLa) and 7g (IC50 = 0.783 μM, HeLa) have exhibited excellent activity, which is approximately 10 times better than the commercial drug gefitinib. According to molecular simulation results, the halogen atoms of 6c and 7g on the coumarin ring can form halogen bonds with COX-2, which significantly improves their activity compared to their hit compounds 6a and 7a. However, the key interactions were lost in binding with COX-1. The calculation results revealed that the two compounds are selective COX-2 inhibitors, with potential selectivity indexes of 6-fold and 5-fold, respectively. The cell-based activity of compounds 6c and 7g toward HEK293 cells demonstrates that our compounds possess an acceptable safety toward normal cells. The results indicate that 6c and 7g can serve as potential lead compounds for further lucubrate.
ACS OmegaChemical Engineering-General Chemical Engineering
CiteScore
6.60
自引率
4.90%
发文量
3945
审稿时长
2.4 months
期刊介绍:
ACS Omega is an open-access global publication for scientific articles that describe new findings in chemistry and interfacing areas of science, without any perceived evaluation of immediate impact.