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P2X7R is a relatively unique ligand\u2010gated ion channel, which is over\u2010expressed in most tumor cells. The activated P2X7R facilitates the tumor growth, invasion, and metastasis. Inhibition of the P2X7R activation can be applied as a potential anti\u2010tumor therapy strategy. There are currently no anti\u2010tumor agents against P2X7R, though several P2X7R antagonists for indications such as anti\u2010inflammatory and anti\u2010depression were reported. In this study, we combined homology modeling (HM), virtual screening, and EB intake assay to characterize the structural features of P2X7R and identify several novel antagonists, which were chemically different from any other known P2X7R antagonists. The identified antagonists could effectively prevent the pore opening of P2X7R with IC50 values ranging from 29.14 to 35.34\u00a0\u03bcM. HM model showed the area between ATP\u2010binding pocket, and allosteric sides were hydrophobic and suitable for small molecule interaction. Molecular docking indicated a universal binding mode, of which residues R294 and K311 were used as hydrogen bond donors to participate in antagonist interactions. The binding mode can potentially be utilized for inhibitor optimization for increased affinity, and the identified antagonists can be further tested for anti\u2010cancer activity or may serve as chemical agents to study P2X7R related functions.<\/jats:p>","DOI":"10.1111\/cbdd.13867","type":"journal-article","created":{"date-parts":[[2021,5,16]],"date-time":"2021-05-16T02:35:17Z","timestamp":1621132517000},"page":"192-205","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of novel P2X7R antagonists by using structure\u2010based virtual screening and cell\u2010based assays"],"prefix":"10.1111","volume":"98","author":[{"given":"Yunshuo","family":"Zhao","sequence":"first","affiliation":[{"name":"School of Life Sciences Zhengzhou University Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life 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