Book of Abstracts: Albany 2007
June 19-23 2007
Pharmacophore Pattern Identification for NK-2 Receptor Agonists and Modeling of the Agonist-binding Site in NK-2 Receptor
The Neurokinin-2 receptor is a member of the Rhodopsin family of G-protein coupled receptors, which represents one of the most relevant target families in small-molecule drug design. NK-2 receptors have been implicated to play a pathophysiological role in asthma. Activation of NK-2 receptor by its endogenous peptide agonist, tachykinins, is associated with diverse biological responses like bronchoconstriction, vasodepression, and regulation of endocrine functions. Agonist binding to the receptor is a crucial event in initiating signaling and, therefore, characterization of the structural features of the agonists can reveal the molecular basis of receptor activation and help in rational design of novel therapeutics. In this study, three-dimensional structures adopted by NK-2 selective peptide agonists have been compared and a three dimensional Pharmacophore for recognition of the Neurokinin-2 receptor by endogenous peptide agonists has been identified. A molecular model for the interaction of the primary ligand NKA with its G-protein coupled receptor Neurokinin-2 receptor has been developed. Three-dimensional model for NK-2 receptor has been generated by Homology modeling using Rhodopsin as a template. A knowledge based docking of the NMR derived bioactive conformation of NKA to the receptor has been performed utilizing the ligand binding data obtained from the photoaffinity labeling and site directed mutagenesis studies. Molecular model for the NKA/NK-2 receptor complex, thus, obtained sheds light on the topographical features of the binding pocket of the receptor and provides atomic insight into the biochemical data currently available for the receptor. The results of the Pharmacophore and receptor modeling studies have been used to discuss the molecular determinants for NK-2 receptor selectivity.
Indu R. Chandrashekar1
1School of Life Sciences