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BackgroundDespite the intense work of researchers since the beginning of the pandemic, thepathogenesis of COVID-19 is not yet clearly understood. It is known that SARS-CoV-2 causeschemosensory receptor disorders and exerts its pathogenic effects through this mechanism.The systemic and multi-organ involvement in COVID-19 suggests that the pathogeneticdisorder develops through multiple receptors and signaling pathways. The previousmechanism of COVID-19, based on ACE2 tropism and explained through a single receptor, isinsufficient to explain the pathogenesis of COVID-19 due to the absence of ACE2 receptors inmost of the affected organs. In addition, there is no satisfactory explanation for themechanism by which ACE2-free organs are affected by COVID-19. In this study, we show thatthe SARS-CoV-2 spike protein binds directly to G-protein coupled receptors using molecularinsertion and stimulation analysis. We predict that the blocking of GPCRs by spike protein maybe the reason for the emergence of various organ-specific findings, especially neuroendocrinedisorders, in COVID-19. The intense location of GPCRs in the limbic system, which is the centerof emotional activity in the brain, and the thalamus, hypothalamus, and pituitary gland, whichis the center of neuroendocrine regulation, makes us think that the neuroendocrine tatulumin COVID-19 develops through GPCRs in these regions. The SARS-CoV-2 spike protein may bindto neuroendocrine cells in the brain, olfactory cells in the nasal epithelium, and peripheralendocrine tissues via GPCRs, causing neuroendocrine, hormonal, metabolic, and psychiatricsymptoms in COVID-19, especially smell and taste disorders.MethodologyIn the current study, we used the PatchDock server to run an insertion study of both theGnRHRs and GPCRs protein and the SARS-CoV-2 Spike protein. The crystal structure of theproteins was taken from RSCP ( https://www.rcsb.org/ ) with accession numbers (PDB ID 7BR3and 6P9X, respectively. We obtained the spike crystal structure with the accession number(PDB ID: 6VYB). The proteins are downloaded in PDB format. Spike-receptor protein wasinvestigated to identify conservative residues. Analysis of the binding of Spike protein withGnRHRsand GPCRS proteins to explore Spike's ability to interact with GnRHRs and GPCRs. Abinding site providing information on binding stability MD simulation of the complex,GROMOS96 43a1 force It was performed with the GROMACS 4.5.4 package using theGROMACS package.ResultsMolecular dynamics and molecular docking analysis of the simulations showed a high affinitybetween the Spike protein and both GnRHRs and GPCRs. The results showed that the spikebinds to GnRHRs with binding energy (-1424.7 k.cal/mol) and GPCRS with binding energy (-1451.8 k.cal/mol). The results obtained confirmed that the local model binds to GPCRS withthe highest insertion score (-1451.8) compared with other GNRHRScomplexes with the lowestbinding affinity, as evidenced by the insertion score (-1424.9). These results indicate betterconjugation of GnRHRs to the binding pocket of the spike receptor in the spike protein's RDB.A comparison of the binding free energy of GPCRS with GnRHRs showed that the GnRHRsprotein was found to bind to vital residues in the RBD of the spike protein. The study ofmolecular dynamics (MD) simulations revealed significant stability of the pike protein withindividual GnRHRsand GPCRS up to 100 ns. |
