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PDK3 plays a central role in cancer through the reversible phosphorylation of PDC thereby blocking the entry of pyruvate into the TCA cycle. PDK3 mediated metabolic switching can be therapeutically targeted for glycolysis addicted cancers.

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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 towards 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 -11.776 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 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 are required before using aminoglycosides as an anti-COVID-19 agent.