Identification of New Human P2X7 Antagonists Using Ligand- and Structure-Based Virtual Screening
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22310%2F25%3A43932933" target="_blank" >RIV/60461373:22310/25:43932933 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acs.jcim.5c00552" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jcim.5c00552</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jcim.5c00552" target="_blank" >10.1021/acs.jcim.5c00552</a>
Alternative languages
Result language
angličtina
Original language name
Identification of New Human P2X7 Antagonists Using Ligand- and Structure-Based Virtual Screening
Original language description
P2X7 receptors, a subtype of ATP-gated cation channel, have gained attention due to their involvement in inflammatory and neurodegenerative diseases, chronic pain, and cancer. However, despite extensive medicinal chemistry efforts, no P2X7 antagonists have reached clinical approval due to suboptimal pharmacokinetic properties, poor selectivity, and insufficient efficacy in comparison to placebo controls. To address these challenges, we employed a virtual screening workflow integrating ligand-based and structure-based approaches to identify novel P2X7 allosteric antagonists. A 3D pharmacophore model derived from three known P2X7 antagonists (A740003, A804598, and JNJ47965567) was used to filter four libraries of commercially available compounds (approximately 10,000,000 total). These compounds were docked into a human P2X7 homology model and ranked by four distinct scoring functions. Eleven compounds were selected based on drug-like properties and key interactions with residues lining the target pocket. Among those, six compounds inhibited P2X7 activation in a YO-PRO 1 dye uptake assay (30 mu M), while just two of those (2 and 9) were also active in a Membrane Potential Red assay (10 mu M). Further screening of 10 analogues of 2 and 9 led to the identification of 2g, which displayed comparable potency (IC50 = 1.31 mu M) to 2 (IC50 = 1.88 mu M) in the YO-PRO 1 dye uptake assay. Docking studies of 2g within the negative allosteric pocket provided insights into its binding mode and key interacting residues. These findings offer a promising starting point for the development of optimized P2X7 antagonists.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10201 - Computer sciences, information science, bioinformathics (hardware development to be 2.2, social aspect to be 5.8)
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Chemical Information and Modeling
ISSN
1549-9596
e-ISSN
1549-960X
Volume of the periodical
65
Issue of the periodical within the volume
13
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
7143-7155
UT code for WoS article
001517698800001
EID of the result in the Scopus database
2-s2.0-105009437563