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?:abstract
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The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved Taking the advantage of a recently released crystal structure of COVID-19 protease in complex with a covalently-bonded inhibitor, N3, su1 /suconducted virtual docking screening of approved drugs and drug candidates in clinical trials For the todocking hits, then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-SA-WSAS su2-4 /suSeveral promising known drugs stand out as potential inhibitors of COVID-19 protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-SA-WSAS binding free energy, -13 82 kcal/mol Streptomycin, an antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3 82 kcal/mol) is not nearly as low as that of the neutral form (-7 92 kcal/mol) One bioactive, PubChem 23727975, has a binding free energy of -12 86 kcal/mol Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified found that one hotspot residue HIS41, is a conserved residue across many viruses including COVID-19, SARS, MERS, and HCV The findings of this study can facilitate rational drug design targeting the COVID-19 protease /
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