In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

An in silico Molecular Dynamics (MD) docking investigation with 4,634 drugs was conducted to identify potential repurposing for therapeutic treatment of Covid-19 disease following SARS-CoV-2 infection. Ligands were ranked according to their binding potential energy in the active site of SARS-CoV-2 protease 3CLpro. Results indicate that the top 10 investigational and experimental drugs with binding energy (BE)<–9 kcal/mol were Lorecivivint, Tivantinib, Omipalisib, DrugBank B08450, SRT-2104, R-428, DrugBank B01897, Bictegravir, Ridinilazole, and Itacitinib, while the top 10 approved drugs with BE< –8.2 were Olaparib, Etoposide, Ouabain, Indinavir, Idelalisib, Trametinib, Lumacaftor, Ergotamine, Canagliflozin, and Edoxaban. There were two antivirals among the top 30 hits, which were Bictegravir (investigational) and Indinavir (approved). Toxicology prediction indicates that only 20% (6/30) of the top ligands were “drug-like,” and none were “leadlike.” Another observation was that the natural flavonoid Diosmin (DrugBank ID B08995), which is a supplement that can be used without prescription for varicose veins, ranked 22 overall (out of 3,896 with BE<–6) with a strong BE = –8.8, and formed 9 hydrogen bonds with the active site for the putative best pose. The clinical relevance for repurposing our top hits requires additional in vitro and in vivo experimentation involving hit-testing, animal studies, transgenics, and xenograft models. If genetic variants of SARS-CoV-2 eventually result in episodic waves of an annual flu (similar to Type A influenza), then human clinical trials focusing on inhibition of SARS-CoV-2 with repurposed drugs will likely become more frequent