Background
Despite the intense work of researchers since the beginning of the pandemic, the
pathogenesis of COVID-19 is not yet clearly understood. It is known that SARS-CoV-2 causes
chemosensory receptor disorders and exerts its pathogenic effects through this mechanism.
The systemic and multi-organ involvement in COVID-19 suggests that the pathogenetic
disorder develops through multiple receptors and signaling pathways. The previous
mechanism of COVID-19, based on ACE2 tropism and explained through a single receptor, is
insufficient to explain the pathogenesis of COVID-19 due to the absence of ACE2 receptors in
most of the affected organs. In addition, there is no satisfactory explanation for the
mechanism by which ACE2-free organs are affected by COVID-19. In this study, we show that
the SARS-CoV-2 spike protein binds directly to G-protein coupled receptors using molecular
insertion and stimulation analysis. We predict that the blocking of GPCRs by spike protein may
be the reason for the emergence of various organ-specific findings, especially neuroendocrine
disorders, in COVID-19. The intense location of GPCRs in the limbic system, which is the center
of emotional activity in the brain, and the thalamus, hypothalamus, and pituitary gland, which
is the center of neuroendocrine regulation, makes us think that the neuroendocrine tatulum
in COVID-19 develops through GPCRs in these regions. The SARS-CoV-2 spike protein may bind
to neuroendocrine cells in the brain, olfactory cells in the nasal epithelium, and peripheral
endocrine tissues via GPCRs, causing neuroendocrine, hormonal, metabolic, and psychiatric
symptoms in COVID-19, especially smell and taste disorders.
Methodology
In the current study, we used the PatchDock server to run an insertion study of both the
GnRHRs and GPCRs protein and the SARS-CoV-2 Spike protein. The crystal structure of the
proteins was taken from RSCP ( https://www.rcsb.org/ ) with accession numbers (PDB ID 7BR3
and 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 was
investigated to identify conservative residues. Analysis of the binding of Spike protein with
GnRHRsand GPCRS proteins to explore Spike's ability to interact with GnRHRs and GPCRs. A
binding 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 the
GROMACS package.
Results
Molecular dynamics and molecular docking analysis of the simulations showed a high affinity
between the Spike protein and both GnRHRs and GPCRs. The results showed that the spike
binds 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 with
the highest insertion score (-1451.8) compared with other GNRHRScomplexes with the lowest
binding affinity, as evidenced by the insertion score (-1424.9). These results indicate better
conjugation 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 GnRHRs
protein was found to bind to vital residues in the RBD of the spike protein. The study of
molecular dynamics (MD) simulations revealed significant stability of the pike protein with
individual GnRHRsand GPCRS up to 100 ns.