Targeting the vital non-structural proteins (NSP12, NSP7, NSP8 and NSP3) from SARS-CoV-2 and inhibition of RNA polymerase by natural bioactive compound naringenin as a promising drug candidate against COVID-19

Elahe Aleebrahim-Dehkordi; Hamed Ghoshouni; Pooneh Koochaki; Mohsen Esmaili-Dehkordi; Elham Aleebrahim; Fatemeh Chichagi; Ali Jafari; Sara Hanaei; Ehsan Heidari-Soureshjani; Nima Rezaei

doi:10.1016/j.molstruc.2023.135642

Targeting the vital non-structural proteins (NSP12, NSP7, NSP8 and NSP3) from SARS-CoV-2 and inhibition of RNA polymerase by natural bioactive compound naringenin as a promising drug candidate against COVID-19

J Mol Struct. 2023 Sep 5:1287:135642. doi: 10.1016/j.molstruc.2023.135642. Epub 2023 Apr 26.

Authors

Elahe Aleebrahim-Dehkordi^{1

2

3}, Hamed Ghoshouni⁴, Pooneh Koochaki⁵, Mohsen Esmaili-Dehkordi⁶, Elham Aleebrahim⁷, Fatemeh Chichagi⁸, Ali Jafari^{2

9

10}, Sara Hanaei^{11

12}, Ehsan Heidari-Soureshjani^{13

14}, Nima Rezaei^{11

12

15}

Affiliations

¹ Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
² Nutritional Health Team (NHT), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
³ Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
⁴ Medical student, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
⁵ Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Pharmacologist, Shahrekord, Iran.
⁷ PhD Student in Food Sciences and Engineering, Islamic Azad University, Tehran North Branch, Tehran, Iran.
⁸ Research Development Center, Sina Hospital, Tehran University of Medical Science, Tehran, Iran.
⁹ Student Research Committee, Department of Nutrition, School of Health, Golestan University of Medical Sciences, Gorgan, Iran.
¹⁰ Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.
¹¹ School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
¹² Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
¹³ Department of Biology, Faculty of Science, Shahrekord University, Shahrekord, P. O. Box. 115, Iran.
¹⁴ Central Laboratory, Shahrekord University, Shahrekord, Iran.
¹⁵ Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

The prevalence of SARS-CoV-2-induced respiratory infections is now a major challenge worldwide. There is currently no specific antiviral drug to prevent or treat this disease. Infection with COVID-19 seriously needs to find effective therapeutic agents. In the present study, naringenin, as a potential inhibitor candidate for RNA Polymerase SARS-CoV-2 was compared with remdesivir (FDA-approved drug) and GS-441,524 (Derivative of the drug remdesivir) by screening with wild-type and mutant SARS-CoV-2 NSP12 (NSP7-NSP8) and NSP3 interfaces, then complexes were simulated by molecular dynamics (MD) simulations to gain their stabilities. The docking results displayed scores of -3.45 kcal/mol and -4.32 kcal/mol against NSP12 and NSP3, respectively. Our results showed that naringenin had ΔG values more negative than the ΔG values of Remdesivir (RDV) and GS-441,524. Hence, naringenin was considered to be a potential inhibitor. Also, the number of hydrogen bonds of naringenin with NSP3 and later NSP12 are more than Remdesivir and its derivative. In this research, Mean root mean square deviation (RMSD) values of NSP3 and NSP12with naringenin ligand (5.55±1.58 nm to 3.45±0.56 nm and 0.238±0.01 to 0.242±0.021 nm, respectively showed stability in the presence of ligand. The root mean square fluctuations (RMSF) values of NSP3 and NSP12 amino acid units in the presence of naringenin in were 1.5 ± 0.31 nm and 0.118±0.058, respectively. Pharmacokinetic properties and prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of naringenin and RDV showed that these two compounds had no potential cytotoxicity.

Keywords: COVID-19; Naringenin; Non-structural proteins; RNA polymerase; Remdesivir; SARS-CoV-2.