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

10.1016/j.jiph.2021.01.016

Research curated

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 (Mpro) 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 Mpro. After HTVS, SP, and XP molecular docking, four high-affinity lead drugs (Iodixanol, Amikacin, Troxerutin, and Rutin) with docking energies −10.629 to −11.776 kcal/mol range were identified. Among them, Amikacin exhibited the lowest Prime/MM-GBSA energy (−73.800 kcal/mol). It led us to evaluate other aminoglycosides (Neomycin, Paramomycin, Gentamycin, Streptomycin, and Tobramycin) against Mpro. All aminoglycosides were bound to the substrate-binding site of Mpro and interacted with crucial residues. Altogether, Amikacin was found to be the most potent inhibitor of Mpro. MD simulations of the Amikacin-Mpro 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.

Source: PubMed

Related molecules

Name	Synonyms	Genes
Amikacin
Gentamicin	Gentamycin
Neomycin	Neo-rx
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Paromomycin
Streptomycin
Tobramycin	Tobrex, Tobi
Iodixanol
Rutin
Proanthocyanidin
Lomitapide
Birinapant
Netilmicin
Lumefantrine
Leuprolide
Cobicistat
Cangrelor
Bortezomib	Velcade, Chemobort, Bortecad
Troxerutin

Related interactions

Target	Drug	Type	Result
3C-like protease	Amikacin	Computational	positive
3C-like protease	Gentamicin	Computational	positive
3C-like protease	Neomycin	Computational	positive
3C-like protease	Paromomycin	Computational	positive
3C-like protease	Streptomycin	Computational	positive
3C-like protease	Tobramycin	Computational	positive
3C-like protease	Iodixanol	Computational	positive
3C-like protease	Rutin	Computational	positive
3C-like protease	Proanthocyanidin	Computational	positive
3C-like protease	Lomitapide	Computational	positive
3C-like protease	Birinapant	Computational	positive
3C-like protease	Netilmicin	Computational	positive
3C-like protease	Lumefantrine	Computational	positive
3C-like protease	Leuprolide	Computational	positive
3C-like protease	Cobicistat	Computational	positive
3C-like protease	Cangrelor	Computational	positive
3C-like protease	Bortezomib	Computational	positive
3C-like protease	Troxerutin	Computational	positive