ABSTRACT
The global emergency caused by COVID-19 makes the discovery of drugs capable of inhibiting SARS-CoV-2 a priority, to reduce the mortality and morbidity of this disease. Repurposing approved drugs can provide therapeutic alternatives that promise rapid and ample coverage because they have a documented safety record, as well as infrastructure for large-scale production. The main protease of SARS-CoV-2 (Mpro) is an excellent therapeutic target because it is critical for viral replication; however, Mpro has a highly flexible active site that must be considered when performing computer-assisted drug discovery. In this work, potential inhibitors of the main protease (Mpro) of SARS-Cov-2 were identified through a docking-assisted virtual screening procedure. A total of 4384 drugs, all approved for human use, were screened against three conformers of Mpro. The ligands were further studied through molecular dynamics simulations and binding free energy analysis. A total of nine currently approved molecules are proposed as potential inhibitors of SARS-CoV-2. These molecules can be further tested to speed the development of therapeutics against COVID-19.
Subject(s)
Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Drug Evaluation, Preclinical , Drug Repositioning , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , COVID-19 , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Humans , Molecular Dynamics Simulation , Pandemics , Protease Inhibitors/chemistry , Protein Conformation , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolismABSTRACT
Introduction. Biological adhesives and effective topical therapeutic agents that improve wound healing are urgently required for the treatment of chronic ulcers. A biodegradable adhesive based on a carbohydrate polymer with zinc oxide (CPZO) was shown to possess anti-inflammatory activity and enhance wound healing, but its bactericidal activity was unknown.Aim. To investigate the bactericidal activity of CPZO against bacteria commonly present as infectious agents in chronic wounds.Methodology. We examined the bactericidal activity of CPZO against three biofilm-producing bacteria (Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) through three strategies: bacterial suspension, biofilm disruption and in vitro wound biofilm model.Results. In suspension cultures, CPZO had direct, potent bactericidal action against S. aureus within 24 h, whereas E. coli took 7 days to be eliminated. By contrast, P. aeruginosa survived up to 14 days with CPZO. CPZO had biofilm disruption activity against clinical isolates of S. aureus in the anti-biofilm test. Finally, in the in vitro wound biofilm model, CPZO dramatically reduced the bacterial viability of S. aureus and P. aeruginosa.Conclusions. Together with its previously shown anti-inflammatory properties, the bactericidal activity of CPZO gives it the potential to be a first-line therapeutic option for chronic various ulcers and, possibly, other chronic ulcers, preventing or controlling microbial infections, and leading to the healing of such complicated chronic ulcers.