title: Constructing an atomic-resolution model of human P2X7 receptor followed by pharmacophore modeling to identify potential inhibitors.
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.
authors: Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors: Mehdi
authors: M
authors: Ahmadi
authors: Pharmaceutical sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors: Amin
authors: A
authors: Nowroozi
authors: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. Electronic address: mohsenshahlaei@yahoo.com.
authors: Mohsen
authors: M
authors: Shahlaei
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D020816:Amino Acid Motifs; D001665:Binding Sites; D057166:High-Throughput Screening Assays; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry*; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate
keywords: Homology modeling; Molecular docking; Molecular dynamics simulation; P2X(7) receptor antagonists; Pharmacophore model; Virtual screening