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.
【저자키워드】 COVID-19, Antibiotics, SARS-CoV-2., Aminoglycosides, Docking and simulation, 【초록키워드】 SARS-CoV-2, pandemic, Antiviral, drugs, molecular docking, clinical trials, Antibiotics, Virtual screening, drug, docking, molecular dynamics, protease, in vitro, rutin, MD simulations, MD simulation, Free energy calculation, free energy, Free energy calculations, Spread, Simulation, molecular, in vivo, inhibitor, interactions, binding, Aminoglycoside, salt, lead, tobramycin, followed by, hydrogen, streptomycin, iodixanol, troxerutin, Amikacin, complex, M pro, help, residues, hydrogen bonds, drug candidate, van der Waals interactions, Neomycin, salt bridges, approach, lowest, evaluate, clinically, required, screened, exhibited, overcome, suggested, anti-infection, cleaving, van der Waal, 【제목키워드】 in silico, Aminoglycoside, inhibitors of SARS-CoV-2, anti-infection,