Discovering of GPCR and GnRHR as SARS-CoV-2 binding receptors, the Scientific Breakthrough that could explain the mystery of its common symptoms with unknown aetiology. In silico research.
Authors: Elkazzaz Mahmoud Ramadan , Ahmed Amr , Haydara Tamer , Shamkh Israa M , Abo-Amer Yousry Esam-Eldin 
Published: December 2021

Abstract
A common symptoms of COVID-19 is a change or disorder in hormonal balance and olfactory function which may persist after recovery including COVID-19-related anosmia and hypogonadism. Hormonal problems including Hypogonadism and Hypothyrodism are being observed in patients with Covid-19. Rise in cases of hormonal imbalance post COVID recovery is a cause for concern. Moreover, anosmia is a well-tolerated symptom of COVID-19, but their etiology isn't understood. The studies demonstrated that the new coronavirus could affect the central nervous system through the olfactory bulb or blood circulation. Furthermore, in addition to anosmia or hyposmia induction, as well as taste disorders, the virus may cause hormonal imbalance ,headache, eye-ache, earache, dizziness and hallucination. It was showed that G-protein coupled receptors (GPCR) and Gonadotropin-releasing hormone receptors (GnRHR), a subtype of GPCR were expressed sufficiently in olfactory region and hypothalamus as well as the lung Herein by using molecular docking and stimulation analysis, we succeeded to elucidate the direct neuroinvasive route of COVID-19 into the nasal epithelium and human brain cells which may lead to anosmia and hormonal imbalance mainly through the olfactory route by direct binding to G-protein coupled receptors (GPCR). Furthermore, we strongly suspect that binding of COVID-19 to the expressed GPCR in the lung is a main cause of ion changing disruption leading to pulmonary edema and failure. Moreover, we confirmed our results by investigating Gonadotropin-releasing hormone receptors (GnRHR) as a novel binding receptor of COVID-19. In the current study, we used PatchDock server to conduct a docking study of the SARS-CoV-2 Spike protein with both of GnHR and GPCR receptor protein. The structure of the crystal structure of the proteins were retrieved from RSCP (https://www.rcsb.org/ ) with accessions numbers (PDB ID 7BR3 and 6P9X respectively. we obtained the crystal structure of spike with accession number (PDB ID: 6VYB). The proteins are downloaded in the pdb format. The spike - receptor protein was investigated to determine the conservative residues of binding of Spike protein with the GnRHR and GPCR proteins in order to discover the ability of Spike to interact with GnRHR and GPCR receptors. We performed Molecular Dynamics (MD) Simulation to investigate the positional and conformational changes of inhibitor molecule in relation to the binding site that provides insight into the binding stability. MD simulation of the complex was carried out with the GROMACS 4.5.4 package using the GROMOS96 43a1 force field .This analysis of simulations of molecular dynamics and molecular docking showed a high affinity between Spike protein and both of GPCR and GnRHR. Results indicated that the spike binds to GNHR with binding energy (-1424.7 k.cal/mol) and to GPCR with binding energy (-1451.8 k.cal/mol). The obtained results confirmed that the native model binds to GPCR with the highest docking score of -1451.8 when compared to the other GNRHR complexes, which have the lowest binding affinity, as evidenced by the docking score of -1424.9.. These results signifies better conjugation of GNRHR to the binding pocket of the spike receptor in the RDB of the spike protein. Comparing the binding free energy of GPCR to GNRHR showed that the GNRHR protein was found to bind to the vital residues in the RBD of the spike protein. But GPCRs protein were found to bind to RDB in other place in chain B of the spike. CONCLUSIONS The COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. A change or disorder in hormonal balance and olfactory function is a common symptom of COVID-19, but its aetiology is unknown. SARS-CoV-2 was found to bind strongly and directly to both GPCR and GnRHR which expressed sufficiently in olfactory neurons. As a result, we confirm that COVID-19 could use these receptors as a direct neuroinvasive route into human brain cells, potentially leading to long-term neurological complications and hormonal imbalance via the olfactory route. Our findings may also shed a new light on the mechanism of pulmonary edema in COVID-19 patients. Therefore ,we propose that GPCR and is involved in COVID-19 pathophysiology and can be exploited as a potential therapeutic target for COVID-19.