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

Abstract

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 ATP-activated 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 (PDB ID: 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, K-means clustering and sphere exclusion methods. The best predictive 3D-QSAR model resulted in training set R $^{2 }$of 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.