Aminoglycosides as potential inhibitors of SARS-CoV-2 main protease: an in silico drug repurposing study on FDA-approved antiviral and anti-infection agents

Mohammad Z Ahmed; Qamar Zia; Anzarul Haque; Ali S Alqahtani; Omar M Almarfadi; Saeed Banawas; Mohammed S Alqahtani; Keshav L Ameta; Shafiul Haque

doi:10.1016/j.jiph.2021.01.016

Aminoglycosides as potential inhibitors of SARS-CoV-2 main protease: an in silico drug repurposing study on FDA-approved antiviral and anti-infection agents

J Infect Public Health. 2021 May;14(5):611-619. doi: 10.1016/j.jiph.2021.01.016. Epub 2021 Feb 9.

Authors

Mohammad Z Ahmed¹, Qamar Zia², Anzarul Haque³, Ali S Alqahtani⁴, Omar M Almarfadi⁴, Saeed Banawas², Mohammed S Alqahtani⁵, Keshav L Ameta⁶, Shafiul Haque⁷

Affiliations

¹ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: mahmed4@ksu.edu.sa.
² Health and Basic Science Research Centre, Majmaah University, Majmaah 11952, Saudi Arabia; Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia.
³ Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin AbdulAziz University, Al Kharj 11942, Saudi Arabia.
⁴ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁵ Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁶ Department of Chemistry, School of Liberal Arts and Sciences, Mody University of Science and Technology, Lakshmangarh, Rajasthan 332311, India.
⁷ Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia.

Abstract

Background: The emergence and spread of SARS-CoV-2 throughout the world has created an enormous socioeconomic impact. Although there are several promising drug candidates in clinical trials, none is available clinically. Thus, the drug repurposing approach may help to overcome the current pandemic.

Methods: The main protease (M^pro) of SARS-CoV-2 is crucial for cleaving nascent polypeptide chains. Here, FDA-approved antiviral and anti-infection drugs were screened by high-throughput virtual screening (HTVS) followed by re-docking with standard-precision (SP) and extra-precision (XP) molecular docking. The most potent drug's binding was further validated by free energy calculations (Prime/MM-GBSA) and molecular dynamics (MD) simulation.

Results: Out of 1397 potential drugs, 157 showed considerable affinity toward M^pro. After HTVS, SP, and XP molecular docking, four high-affinity lead drugs (Iodixanol, Amikacin, Troxerutin, and Rutin) with docking energies -10.629 to -11.776kcal/mol range were identified. Among them, Amikacin exhibited the lowest Prime/MM-GBSA energy (-73.800kcal/mol). It led us to evaluate other aminoglycosides (Neomycin, Paramomycin, Gentamycin, Streptomycin, and Tobramycin) against M^pro. All aminoglycosides were bound to the substrate-binding site of M^pro and interacted with crucial residues. Altogether, Amikacin was found to be the most potent inhibitor of M^pro. MD simulations of the Amikacin-M^pro complex suggested the formation of a complex stabilized by hydrogen bonds, salt bridges, and van der Waals interactions.

Conclusion: Aminoglycosides may serve as a scaffold to design potent drug molecules against COVID-19. However, further validation by in vitro and in vivo studies is required before using aminoglycosides as an anti-COVID-19 agent.

Keywords: Aminoglycosides; Antibiotics; COVID-19; Docking and simulation; SARS-CoV-2.

MeSH terms

Aminoglycosides
Antiviral Agents / pharmacology
COVID-19*
Drug Repositioning*
Humans
Molecular Docking Simulation
Peptide Hydrolases
Protease Inhibitors / pharmacology
SARS-CoV-2

Substances

Aminoglycosides
Antiviral Agents
Protease Inhibitors
Peptide Hydrolases