Pyrid-2-yl and 2-CyanoPhenyl fused heterocyclic compounds as human P2X_3 inhibitors:a combined approach based on homology modelling, docking and QSAR analysis

摘要

P2X receptors are hetero-oligomeric proteins that function as membrane ion channels and are gated by extracellular ATP. The hP2X_3 subunit is a constituent of the channels on a subset of sensory neurons involved in pain signaling, where ATP released by damaged and inflamed tissue can initiate action potentials. Hence, the inhibition of ATPactivated P2X_3 receptor is an exciting approach for the treatment of inflammatory and neuropathic pain. Recently, the crystal structures of zebrafish P2X_4 (zP2X_4) were obtained in closed, apo state (PDB ID:3I5D) and ATP-bound, open state (PDBID:4DW1). These structures were used to develop a homology model of human P2X_3 (hP2X_3) in order to identify through docking studies, the binding modes of known P2X_3 inhibitors and their key active site interactions, along with a pharmacophore-based 3D-QSAR model for a series of 136 Pyrid-2-yl and 2-CyanoPhenyl fused heterocyclic compounds. These 3D-QSAR models have been developed with different combinations of training and test set divisions obtained by random separation, Jarvis-Patrick clustering, Kmeans clustering and sphere exclusion methods. The best predictive 3D-QSARmodel resulted in training set R~2of 0.75, internal test set Q~2 of 0.74, Pearson-R value of 0.87 and root mean square error of 0.37. The information generated by the pharmacophore model and docking analyses using the homology model provides valuable clues to design novel potent hP2X_3 inhibitors.