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Chiara B M Platania, Federica Geraci, Filippo Drago, Claudio Bucolo; Exploring ligands selectivity toward human P2X7 receptor: application to drug discovery in ophthalmology. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© 2017 Association for Research in Vision and Ophthalmology.
To investigate the molecular features of ligand selectivity toward the purinergic P2X7 receptor, in order to carry out rational structure based drug discovery campaign in ophthalmology.
Homology modeling of human P2X7 and P2X4 receptors, in the closed and open conformations, was carried out using as templates the structures of closed and open zfP2X4 (PDB:4DW0 and PDB:4DW1 respectively). The hP2X4 receptor was included because it can be blocked by the P2X7 antagonist Brilliant Blue G (BBG). The binding of P2X7 antagonists, BBG and MRS2540, to hP2X7 and hP2X4 models was predicted by means of the molecular docking software Glide (Schrodinger©) and with MM-GBSA re-scoring. SIFt (=structural interaction fingerprint) of P2X7 antagonists was calculated by post-processing of docking of the following compounds: BBG, MRS2540, AZ10606120, AZ116445373, A438079, JNJ47965567, A740003, A804598.
hP2X7 and hP2X4 receptors share high sequence homology and identity (60% and 45% respectively). BBG docked into the orthosteric pocket of closed hP2X7 and hP2X4 receptor had similar predicted affinity: -81.6 and -84.5 kcal/mol. BBG showed high predicted affinity for orthosteric pocket of open P2X7 receptor (-117.3 Kcal/mol), but no output was obtained docking BBG into the orthosteric pocket of P2X4 receptor. MRS2540 had higher affinity for P2X7 receptor in comparison to P2X4, both in closed and open conformations: P2X7 closed (-89.5 kcal/mol), P2X4 closed (-48.2 kcal/mol), P2X7 open (-85.8 kcal/mol), P2X4 open (-65.0 kcal/mol). Best P2X7 antagonists, that clustered together in terms of SIFt, were: BBG, MRS2540, A438079, JNJ7965567, A74003.
The computational approach, hereby described, was successful in characterization of molecular features of selective P2X7 antagonists. In particular, MRS2540 was predicted to have higher selectivity toward hP2X7 receptor in comparison to hP2X4 receptors. Calculated SIFt, based on selective P2X7 antagonists, will guide screening of large compound databases. P2X receptors are expressed in neurons in the inner and outer retina and contribute to visual processing as well as the damage of retinal ganglion cells. Therefore, our approach would help drug discovery of molecules for treatment of retinal degenerative diseases.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Brilliant Blue G and MRS2540 docked into P2X7 and P2X4 receptors
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