Orexin 2 receptor Crosstalk with GLP1 receptor reveals dual therapy for improvement of Sleep deprivation-induced obesity:  An Integrated Network Pharmacology, Molecular Docking and Molecular Dynamics Simulation approach

The Glucagon-Like Peptide-1 Receptor (GLP1R) and the Hypocretin/Orexin Receptor Type 2 (HCRTR2) are critical G protein-coupled receptors that govern metabolism and neuroendocrine function. Clinical observations suggest a functional overlap, particularly in the regulation of appetite, energy homeostasis, and sleep/wake cycles. Sleep disturbance profoundly disrupts neuroendocrine and metabolic homeostasis, contributing to obesity, impaired glucose regulation, elevated appetite, and altered reward signalling. This study employed an integrated computational approach, combining Network Pharmacology, Molecyular Docking, and Molecular Dynamics simulations to elucidate the molecular crosstalk and predict the structural basis for dual-target modulation. Network Pharmacology analysis of target genes revealed a significant overlap of 51 common targets between GLP-1R and HCRTR2. which were enriched in Gene Ontology terms related to cAMP-mediated signalling, circadian regulation, synaptic vesicle organisation, and peptide hormone binding. KEGG pathway enrichment revealed significant clustering in dopaminergic reward pathways, adipocytokine signalling, and lipid-metabolic regulation, indicating shared involvement in neuroendocrine and metabolic homeostasis. To validate this convergence structurally, cross-docking of cognate Ligands was performed using the Schrödinger suite on 7LCJ and 4S0V. The core experiments involved cross-docking the GLP-1R agonist, Danuglipron, with HCRTR2, and the established Orexin antagonist, Suvorexant, with GLP-1R. Both cross-docking pairs showed favourable binding affinities. The stability of both cross-docked complexes was further confirmed via Molecular dynamics simulation, which demonstrated low-deviation dynamics and persistent binding interactions. These results provide strong molecular and structural evidence that the GLP-1R and HCRTR2 signalling axes converge on common molecular hubs, offering an atomic-level mechanism for their functional interdependence and explaining potential polypharmacological effects of existing drugs. This is the first of its kind, comprehensive in silico framework demonstrating molecular convergence between GLP-1R and HCRTR2.