Molecular modeling studies on the human neuropeptide S receptor and its antagonists.

Neuropeptide S (NPS) is a 20-residue peptide of great interest due to its potential involvement in several biological processes such as arousal, anxiety, and food intake. The NPS receptor belongs to the rhodopsin-like G-protein-coupled receptor superfamily, and several polymorphisms and isoforms of this receptor are associated with asthma, allergies, and bronchial hyperresponsiveness, in particular the Asn107 Ile mutation. Limited tructural information is available for this peptide–receptor system, particularly regarding the NPS receptor structure, its nonpeptide ligands, and the molecular aspects of agonist and antagonist binding processes. In this work, rhodopsin-based homology models of the NPS receptor and its Asn107 Ile variant were built and refined in a membrane bilayer model, and binding modes for nonpeptide antagonists were simulated. This study provides the first structural study of the human NPS receptor, and the results provide a starting point for further characterization of the binding modes of its antagonists, and or the rational design of new NPS receptor ligands.