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

Abstract

A in silico molecular dynamics (MD) docking investigation was conducted to identify drugs (ligands) which could potentially be of interest for repurposing. We sought ligands which formed the strongest binding potential energy with the x-ray crystallography-based active site of the SARS-CoV-2 protease C3Lpro. A total of 11,013 ligands were obtained from DrugBank. Because of the larger size of the active site of 3CLpro, we chose ligands whose molecular weight (MW) was greater than 400 (daltons) and less than 700, which resulted in 5,920 ligands. After correction of bonds and hydrogens, there were 4,634 ligands available for docking. Docking 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 antiviral drugs among the top 30 hits, which were Bictegravir (investigational) and Indinavir (approved). The top 10 antivirals with BE≤-8.2 were Bictegravir, Tegobuvir, Filibuvir, Saquinavir, Fostemsavir, Indinavir, Temsavir, Pimodivir, Amenamevir, and Doravirine. Interestingly, the antiviral Remdesavir ranked low among the top 30 antivirals, since its BE was a low value of -7.5 kcal/mol. In silico toxicology and ADME (absorption, distribution, metabolism, excretion) prediction indicates that only 20% (6/30) of the top ligands were “drug-like,” and none were “lead-like,” since the lower bound of MW was 400. Another interesting finding was that the investigational natural supplement Diosmin (DrugBank ID B08995), used without prescription for varicose veins, ranked 22 overall (out of 3,896 with BE≤-6) with a strong BE=-8.8, and formed 8 hydrogen bonds with the active site for the putative best pose. Its energy-minimized 3D structure deeply penetrated and fully covered the width of the active site’s pocket. Diosmin had a lower BE than 97% of the top 30 antiviral drugs and formed more hydrogen bonds with the active site than 93% of the top 30 antivirals. Diosmin could therefore potentially serve as a strong inhibitor of the 3CLpro protease of SARS-CoV-2 and could be investigated in human clinical trials. Since a prescription is not required for its use, it could also be explored as a self-medicating natural alternative to prescribed synthetic drugs. Lastly, the green tea component epigallocatechin gallate (DrugBank ID B12116) also had a low BE=-8.3, and formed 2 hydrogen bonds with the active site, which was a BE that was better than 70% of the top 30 antivirals.