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Identification of novel P2X7R antagonists by using structure‐based virtual screening and cell‐based assays
Author(s) -
Zhao Yunshuo,
Chen Xiaotong,
Lyu Sifan,
Ding Zhe,
Wu Yahong,
Gao Yanfeng,
Du Jiangfeng
Publication year - 2021
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13867
Subject(s) - allosteric regulation , virtual screening , docking (animal) , receptor , antagonist , chemistry , tumor microenvironment , homology modeling , binding site , microbiology and biotechnology , biochemistry , drug discovery , biophysics , cancer research , biology , enzyme , tumor cells , medicine , nursing
In the tumor microenvironment, inflammation and necrosis cause the accumulations of ATP extracellularly, and high concentrations of ATP can activate P2X7 receptors (P2X7R), which leads to the influx of Na + , K + , or Ca 2+ into cells and trigger the downstream signaling pathways. P2X7R is a relatively unique ligand‐gated ion channel, which is over‐expressed 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‐tumor therapy strategy. There are currently no anti‐tumor agents against P2X7R, though several P2X7R antagonists for indications such as anti‐inflammatory and anti‐depression 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 μM. HM model showed the area between ATP‐binding 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‐cancer activity or may serve as chemical agents to study P2X7R related functions.