ABSTRACT
Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of -6.7 kcal/mol compared with the -6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.
Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Protease Inhibitors/pharmacology , Selenium/analysis , Antiviral Agents/chemistry , Computational Biology , Computer Simulation , Coronavirus 3C Proteases/chemistry , Heterocyclic Compounds/chemistry , Humans , Ligands , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protein Structure, Tertiary , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Reproducibility of Results , Sulfonic AcidsABSTRACT
A pandemic caused by the novel coronavirus (SARS-CoV-2 or COVID-19) began in December 2019 in Wuhan, China, and the number of newly reported cases continues to increase. More than 19.7 million cases have been reported globally and about 728,000 have died as of this writing (10 August 2020). Recently, it has been confirmed that the SARS-CoV-2 main protease (Mpro) enzyme is responsible not only for viral reproduction but also impedes host immune responses. The Mpro provides a highly favorable pharmacological target for the discovery and design of inhibitors. Currently, no specific therapies are available, and investigations into the treatment of COVID-19 are lacking. Therefore, herein, we analyzed the bioactive phytocompounds isolated by gas chromatography-mass spectroscopy (GC-MS) from Tinospora crispa as potential COVID-19 Mpro inhibitors, using molecular docking study. Our analyses unveiled that the top nine hits might serve as potential anti-SARS-CoV-2 lead molecules, with three of them exerting biological activity and warranting further optimization and drug development to combat COVID-19.
Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/chemistry , Phytochemicals/chemistry , Protease Inhibitors/chemistry , Tinospora/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/classification , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Drug Discovery , Gas Chromatography-Mass Spectrometry , Gene Expression , Humans , Kinetics , Molecular Docking Simulation , Pandemics , Phytochemicals/classification , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Pneumonia, Viral/drug therapy , Protease Inhibitors/classification , Protease Inhibitors/isolation & purification , Protease Inhibitors/pharmacology , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , SARS-CoV-2 , Substrate Specificity , Thermodynamics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolismABSTRACT
AIMS: With a large number of fatalities, coronavirus disease-2019 (COVID-19) has greatly affected human health worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes COVID-19. The World Health Organization has declared a global pandemic of this contagious disease. Researchers across the world are collaborating in a quest for remedies to combat this deadly virus. It has recently been demonstrated that the spike glycoprotein (SGP) of SARS-CoV-2 is the mediator by which the virus enters host cells. MAIN METHODS: Our group comprehensibly analyzed the SGP of SARS-CoV-2 through multiple sequence analysis and a phylogenetic analysis. We predicted the strongest immunogenic epitopes of the SGP for both B cells and T cells. KEY FINDINGS: We focused on predicting peptides that would bind major histocompatibility complex class I. Two optimal epitopes were identified, WTAGAAAYY and GAAAYYVGY. They interact with the HLA-B*15:01 allele, which was further validated by molecular docking simulation. This study also found that the selected epitopes are able to be recognized in a large percentage of the world's population. Furthermore, we predicted CD4+ T-cell epitopes and B-cell epitopes. SIGNIFICANCE: Our study provides a strong basis for designing vaccine candidates against SARS-CoV-2. However, laboratory work is required to validate our theoretical results, which would lay the foundation for the appropriate vaccine manufacturing and testing processes.