In Silico Discovery of GPCRs and GnRHRs as Novel Binding Receptors of SARS-CoV-2 Spike Protein Could Explain Neuroendocrine Disorders in COVID-19

• Published in: Vaccines (Basel) 2022-09, Vol.10 (9), p.1500
• Main Authors: Elkazzaz, Mahmoud, Ahmed, Amr, Abo-Amer, Yousry Esam-Eldin, Hydara, Tamer, Haikal, Abdullah, Razek, Dina N. Abd El, Eltayb, Wafa Ali, Wang, Xiling, Karpiński, Tomasz M, Hamza, Dalia, Jabbar, Basit, Shamkh, Israa M
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin; Angiotensin-converting enzyme 2; Binding; Binding sites; Coronaviruses; COVID-19; Development and progression; Dynamic stability; Endocrine gland diseases; G protein-coupled receptors; Genetic engineering; GnRHR; Gonadotropin-releasing hormone; Gonadotropins; GPCR; Molecular docking; Molecular dynamics; Nervous system diseases; Olfactory neurons; Organs; Pandemics; Pathogenesis; Peptidyl-dipeptidase A; Pituitary (anterior); Proteins; Receptors; Severe acute respiratory syndrome coronavirus 2; Signal transduction; Signs and symptoms; Simulation; Spike protein; Stability analysis; Therapeutic targets; Tropism; Viral diseases; Viruses
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines10091500

Despite the intense research work since the beginning of the pandemic, the pathogenesis of COVID-19 is not yet clearly understood. The previous mechanism of COVID-19, based on ACE2 tropism and explained through a single receptor, is insufficient to explain the pathogenesis due to the absence of angiotensin-converting enzyme 2 (ACE2) receptors in most of the affected organs. In the current study, we used the PatchDock server to run a molecular docking study of both the gonadotropin-releasing hormone receptor (GnRHR) and G-protein-coupled-receptor (GPCR) with the SARS-CoV-2 spike protein. Molecular Dynamics (MD) simulations were run to analyze the stability of the complexes using the GROMACS package. The docking results showed a high affinity between the spike protein with the GnRHR (−1424.9 kcal/mol) and GPCR (−1451.8 kcal/mol). The results of the MD simulations revealed the significant stability of the spike protein with the GnRHR and GPCR up to 100 ns. The SARS-CoV-2 spike protein had strong binding interactions with the GPCRs and GnRHRs, which are highly expressed in the brain, endocrine organs, and olfactory neurons. This study paves the way towards understanding the complex mechanism of neuroendocrine involvement and peripheral organ involvement, may explain the changing symptoms in patients due to new variants, and may lead to the discovery of new drug targets for COVID-19. In vitro studies involving genetic engineering or gene knockdown of the GPCRs and GnRHRs are needed to further investigate the role of these receptors in COVID-19 pathogenesis.