Dataset Information

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

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.

SUBMITTER: Ahmed MZ

PROVIDER: S-EPMC7871101 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

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

Ahmed Mohammad Z MZ Zia Qamar Q Haque Anzarul A Alqahtani Ali S AS Almarfadi Omar M OM Banawas Saeed S Alqahtani Mohammed S MS Ameta Keshav L KL Haque Shafiul S

Journal of infection and public health 20210209 5

<h4>Background</h4>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.<h4>Methods</h4>The main protease (M<sup>pro</sup>) of SARS-CoV-2 is crucial for cleaving nascent polypeptide chains. Here, FDA-approved antiviral and anti-infection drugs were screened by high- ...[more]

PMID: 33866129

Similar Datasets

Project description:Coronaviruses are enveloped positive-strand RNA viruses belonging to family Coronaviridae and order Nidovirales which cause infections in birds and mammals. Among the human coronaviruses, highly pathogenic ones are Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) which have been implicated in severe respiratory syndrome in humans. There are no approved antiviral drugs or vaccines for the treatment of human CoV infection to date. The recent outbreak of new coronavirus pandemic, coronavirus disease 2019 (COVID-19) has caused a high mortality rate and infections around the world which necessitates the need for the discovery of novel anti-coronaviral drugs. Among the coronaviruses proteins, 3C-like protease (3CLpro) is an important drug target against coronaviral infection as the auto-cleavage process catalysed by the enzyme is crucial for viral maturation and replication. The present work is aimed at the identification of suitable lead molecules for the inhibition of 3CLpro enzyme via a computational screening of the Food and Drug Administration (FDA) approved antiviral drugs and phytochemicals. Based on binding energies and molecular interaction studies, we shortlisted five lead molecules (both FDA approved drugs and phytochemicals) for each enzyme targets (SARS-CoV-2 3CLpro, SARS-CoV 3CLpro and MERS-CoV 3CLpro). The lead molecules showed higher binding affinity compared to the standard inhibitors and exhibited favourable hydrophobic interactions and a good number of hydrogen bonds with their respective targets. A few promising leads with dual inhibition potential were identified among FDA approved antiviral drugs which include DB13879 (Glecaprevir), DB09102 (Daclatasvir), molecule DB09297 (Paritaprevir) and DB01072 (Atazanavir). Among the phytochemicals, 11,646,359 (Vincapusine), 120,716 (Alloyohimbine) and 10,308,017 (Gummadiol) showed triple inhibition potential against all the three targets and 102,004,710 (18-Hydroxy-3-epi-alpha-yohimbine) exhibited dual inhibition potential. Hence, the proposed lead molecules from our findings can be further investigated through in vitro and in vivo studies to develop into potential drug candidates against human coronaviral infections.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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