In silico discovery of GPCRSs and GnRHRs as Novel SARS-CoV-2 binding receptors, the Scientific Breakthrough that could explain the observed High cortisol, Appetite loss, Ansomnia and Hypogonadism, as well as Hypothyroidism, Retinol deficiency and menstrual disturbances among SARS-COV-2 patients.
Authors: Elkazzaz Mahmoud Ramadan , Ahmed Amr , Alshuwaier Ghareeb , Shamkh Israa M , Abo-Amer Yousry Esam-Eldin , Haydara Tamer 
Published: December 2021

Abstract
Background COVID-19 is known to cause chemosensory dysfunction. A common symptoms of COVID-19 is a disorder in hormonal balance and olfactory function which may persist after recovery including COVID-19-related anosmia and hypogonadism. Hormonal problems such as 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 aetiology 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 Appetite loss, High cortisol, Anxiety ,Retinol deficiency, Eye-ache, earache, Dizziness, Memory, Minstrual disturbances and hallucination. G-protein coupled receptors (GPCRSs) are well known to be expressed throughout the body, and they represent the genome's largest superfamily of signaling. It was showed that G-protein coupled receptors (GPCRS) and Gonadotropin-releasing hormone receptors (GnRHRs, a subtype of GPCRS), were expressed sufficiently in olfactory region and hypothalamus as well as thyroid gland and the human lung. It was found that GPCRs are responsible for diverse biological functions such as Appetite, Cortisol level, Smelling and Tasting regulation as well as Retinol transport and act as receptors of Thyroxin. 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 (GPCRS). Furthermore, we strongly suspect that binding of COVID-19 to the expressed GPCRS 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 (GnRHRs) as a novel binding receptor of COVID-19.MethodologyIn the current study, we used PatchDock server to conduct a docking study of the SARS-CoV-2 Spike protein with both of GnRHRs and GPCRSs 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 GnRHRs and GPCRS 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 the included proteins 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.ResultsThis analysis of simulations molecular dynamics and molecular docking showed a high affinity between Spike protein and both of GnRHRs and GPCRSs . Results indicated that the spike binds to GNRHRS with binding energy (-1424.7 k.cal/mol) and to GPCRS with binding energy (-1451.8 k.cal/mol). The obtained results confirmed that the native model binds to GPCRS with the highest docking score of ( -1451.8) when compared to the other GNRHRS complexes, which have the lowest binding affinity, as evidenced by the docking score of (-1424.9). These results signifies better conjugation of GNRHRS to the binding pocket of the spike receptor in the RDB of the spike protein . Comparing the binding free energy of GPCRS to GNRHRS showed that the GNRHRS protein was found to bind to the vital residues in the RBD of the spike protein. But GPCRSs protein were found to bind to new RDB in other place in chain B of the spike. The molecular dynamics (MD) simulations study revealed significant stability of s pike protein with the GnRHRs and GPCRS separately up to 50 ns.CONCLUSIONSThe 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 as well as Appetite loss and retinol deficiency , but its aetiology is unknown. SARS-CoV-2 was found to bind strongly and directly to both GPCRS and GnRHRs which expressed sufficiently in olfactory neurons. As a result, we confirm that COVID-19 could use these receptors especially GNRHRS as a direct neuroinvasive route into human brain cells, potentially leading to long-term neurological complications and hormonal imbalance in addition to Appetite loss and retinol deficiency 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 GPCRS and is involved in COVID-19 pathophysiology and can be exploited as a potential therapeutic target for COVID-19.