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 -11.776kcal/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 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.