Identification of New Human P2X7 Antagonists Using Ligand- and Structure-Based Virtual Screening

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Identification of New Human P2X7 Antagonists Using Ligand- and Structure-Based Virtual Screening

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Identification of New Human P2X7 Antagonists Using Ligand- and Structure-Based Virtual Screening

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10201 - Computer sciences, information science, bioinformathics (hardware development to be 2.2, social aspect to be 5.8)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Chemical Information and Modeling

ISSN

1549-9596

e-ISSN

1549-960X

Svazek periodika

65

Číslo periodika v rámci svazku

13

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

7143-7155

Kód UT WoS článku

001517698800001

EID výsledku v databázi Scopus

2-s2.0-105009437563