Targeting schizophrenia-associated GPCRs: An integrative network pharmacology, molecular docking, and simulation study of

Schizophrenia remains a major cause of disability worldwide, and current antipsychotic treatments are associated with variable therapeutic response and adverse effects. In this study, four aporphine alkaloids from Nelumbo nucifera, namely nuciferine, nornuciferine, dehydronuciferine and 7-HDNF were evaluated in silico for their potential interactions with schizophrenia-associated G-protein-coupled receptors (GPCRs). Drug-likeness and ADMET profiling indicated that the four alkaloids complied with Lipinski’s Rule of Five and exhibited a low topological polar surface area, together with favorable predicted blood–brain barrier related properties. Network pharmacology integrating multiple target- and disease-gene resources identified neuronal and GPCR-associated functional enrichment, with DRD2, HTR2A and HTR2C emerging as shared targets among predicted alkaloid targets, schizophrenia-associated genes and clinically relevant antipsychotic targets. Molecular docking showed predicted interactions of all four alkaloids with DRD2 and HTR2A, with binding affinities lower than those of the reference ligands spiperone and zotepine. Molecular dynamics simulations provided exploratory information on the conformational behavior of selected alkaloid–receptor complexes under the applied simulation conditions, while MM/PBSA calculations provided approximate energetic estimates. HTR2A complexes generally exhibited lower protein backbone fluctuations than DRD2 complexes, whereas the DRD2 complexes showed greater conformational variation. Among the alkaloids, nuciferine and 7-HDNF showed relatively favorable predicted energetic profiles for DRD2 and HTR2A, respectively. Overall, the findings provide a computational basis for prioritizing N. nucifera aporphine alkaloids for further investigation of their interactions with schizophrenia-relevant GPCRs. Experimental studies on receptor binding, functional and pharmacological aspects are required to determine their affinity, efficacy, signaling properties and therapeutic relevance.