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

Mahmoud Elkazzaz; Amr Ahmed; Yousry Esam-Eldin Abo-Amer; Tamer Hydara; Abdullah Haikal; Dina N Abd El Razek; Wafa Ali Eltayb; Xiling Wang; Tomasz M Karpiński; Dalia Hamza; Basit Jabbar; Israa M Shamkh

doi:10.3390/vaccines10091500

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

Vaccines (Basel). 2022 Sep 8;10(9):1500. doi: 10.3390/vaccines10091500.

Authors

Affiliations

¹ Department of Chemistry and Biochemistry, Faculty of Science, Damietta University, Damietta 7952567, Egypt.
² Director of Tuberculosis Ghubera Mobile Team, Public Health Department, First Health Cluster, Ministry of Health, Riyadh 966-11, Saudi Arabia.
³ Hepatology, Gastroenterology, and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, El-Mahalla el-Kubra 31951, Egypt.
⁴ Department of Internal Medicine, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
⁵ Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁶ Department of Biochemistry, Al Menoufia University, Shibin el Kom 32511, Egypt.
⁷ Biotechnology Department, Faculty of Science and Technology, Shendi University, Shendi 11111, Nher Anile, Sudan.
⁸ Chinese Academy of Sciences Key Laboratory of Biofuels and Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao 266000, China.
⁹ Institute of Bioenergy and Bioprocess Technology Chinese Academy of Sciences, Qingdao 266000, China.
¹⁰ Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland.
¹¹ Department of Zoonoses, Faculty of Veterinary Medicine, Cairo University, Giza 12613, Egypt.
¹² Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
¹³ Chemo and Bioinformatics Lab, Bio Search Research Institution BSRI, Botany and Microbiology Department, Faculty of Science, Cairo University, Giza 12613, Egypt.

Abstract

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.

Keywords: ACE2; COVID-19; GPCR; GnRHR; MD simulation; molecular docking; spike protein.

Grants and funding

The authors acknowledge bio search gate company for support through researchers supporting project number (biogate 22877).