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Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Constructing an atomic-resolution model of human P2X7 receptor followed by pharmacophore modeling to identify
Mehdi Ahmadi1, Amin Nowroozi2, Mohsen Shahlaei3
1Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Abstract:
The P2X purinoceptor 7 (P2X7R) is a trimeric ATP-activated ion channel gated by extracellular ATP. P2X7R has important role in numerous diseases including pain, neurodegeneration, and inflammatory diseases such as rheumatoid arthritis and osteoarthritis. In this prospective, the discovery of small-molecule inhibitors for P2X7R as a novel therapeutic target has received considerable attention in recent years. At first, 3D structure of P2X7R was built by using homology modeling (HM) and a 50ns molecular dynamics simulation (MDS). Ligand-based quantitative pharmacophore modeling methodology of P2X7R antagonists were developed based on training set of 49 compounds. The best four-feature pharmacophore model, includes two hydrophobic aromatic, one hydrophobic and one aromatic ring features, has the highest correlation coefficient (0.874), cost difference (368.677), low RMSD (2.876), as well as it shows a high goodness of fit and enrichment factor. Consequently, some hit compounds were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. Among these compounds, six potential molecule were identified as potential virtual leads which, as such or upon further optimization, can be used to design novel P2X7R inhibitors.
Insights
Researchers developed a computational model to discover new P2X7 receptor (P2X7R) inhibitors. This work identified six potential drug candidates for treating pain and inflammatory diseases by targeting P2X7R.
Area of Science:
- Pharmacology
- Computational Chemistry
- Drug Discovery
Background:
- The P2X purinoceptor 7 (P2X7R) is an ATP-activated ion channel implicated in pain, neurodegeneration, and inflammatory conditions like rheumatoid arthritis and osteoarthritis.
- Targeting P2X7R with small-molecule inhibitors presents a promising therapeutic strategy for various diseases.
Purpose of the Study:
- To develop a computational model for identifying novel small-molecule inhibitors of the P2X7 receptor.
- To discover potential drug leads for P2X7R-related diseases through virtual screening and molecular docking.
Main Methods:
- Homology modeling and molecular dynamics simulations were used to build the 3D structure of P2X7R.
- A ligand-based quantitative pharmacophore model was developed using 49 known P2X7R antagonists.
- Virtual screening and molecular docking were employed to identify potential inhibitor candidates.
Main Results:
- A robust four-feature pharmacophore model was established, demonstrating high correlation and goodness of fit.
- Virtual screening and molecular docking identified six potential small-molecule inhibitors of P2X7R.
- These identified compounds serve as promising leads for further optimization and drug design.
Conclusions:
- The developed computational approach is effective for discovering novel P2X7R inhibitors.
- The identified virtual leads hold potential for developing new therapeutics for inflammatory and neurodegenerative diseases.
- This study provides a foundation for the rational design of P2X7R-targeting drugs.
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