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

Peterson, Leif E.

doi:10.2139/ssrn.3580951

Cited by 6 publications

(8 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a similar study, the top hits were predicted to be as low as −8.7 kcal/mol of binding energy for approved drugs. Experimental drugs exhibited binding energies as low as −9.1 kcal/mol [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

Alkhatip

Georgakis²,

Valenzuela³

et al. 2021

IJMS

View full text Add to dashboard Cite

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at −8.3 kcal/mol, followed by Zn and Ca at −8.0 kcal/mol, and Fe and Mg at −7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn–Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

show abstract

Section: Discussionmentioning

confidence: 99%

Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

Alkhatip

Georgakis²,

Valenzuela³

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Several in silico studies suggested that flavonoids such as EGCG, hesperidin, oleuropein, and myricetin could be used as an alternative therapy for SARS-CoV-2 (Peterson, 2020;Khaerunnisa et al, 2020;Meneguzzo et al, 2020;Adem et al, 2020;Rehman MFu et al, 2021). Considering the promising results of the in silico studies, the potential therapeutic and prophylactic effects of plant-isolated natural flavonoids should be further investigated by in vitro studies to reveal their efficiency.…”

Section: Discussionmentioning

confidence: 99%

“…In their in silico docking study of 4634 effective compounds, Leif Peterson found that flavonoids group Diosmin, epigallocatechin gallate, and hidrosmin placed 22 nd , 134 th , and 163 rd , respectively (Peterson, 2020). In another in silico study, Khaerunnisa et al suggested that drugs such as lopinavir and nelfinavir might represent a potential therapy, and luteolin-7-glucoside dimethoxy curcumin, oleuropein, apigenin-7-glucoside, curcumin, catechine, and epicatechin-gallate could be used as Covid-19 M pro inhibitors (Khaerunnisa et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Antiviral Effects of Some Flavonoids on SARS-CoV-2

Kirmizibekmez

Altintaş²,

Arslan³

et al. 2021

Turkish Journal of Science and Health

View full text Add to dashboard Cite

Covid-19 disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a global epidemic that affects millions of lives. To date, there is no definitive cure for the disease and global vaccination efforts with newly produced vaccines will take years to complete. In silico studies have suggested that different flavonoids play an antiviral role against SARS-CoV-2. In this study, based on in silico findings, we examined the in vitro effects of four promising flavonoids, hesperidin, oleuropein, epigallocatechin gallate (EGCG), and myricetin. Material and Methods: Hesperidin, oleuropein, EGCG, and myricetin have been extracted from natural plant sources and purified by using liquid chromatography (LC). Analyses of the cell toxicity and antiviral activity of these four flavonoids at different concentrations against SARS-CoV-2 were done. Results: Our results show that CC50 values for EGCG, hesperidin, myricetin and oleuropein are 38 μg/ml, 25 μg/ml, >200 μg/ml and >200 μg/ml, respectively. In addition, in our hands, neither of the flavonoids we examined has antiviral effects against Sars-CoV-2 virus-infected Vero E6 cells. Our data revealed that all flavonoids we tested have Inhibitory Concentration 50 (IC50) value >200 μg/ml. Conclusion: Our results using the SARS-CoV-2 infected Vero E6 cell model were found to contradict previous in silico findings, and these flavonoids were found to have no antiviral effects in vitro. Studies investigating flavonoids' antiviral activity on SARS-CoV-2 should be directed to those other than oleuropein, hesperidin, EGCG, and myricetin.

show abstract

“…The protease binding of rolitetracycline has been reported by Durdagi (2020) and Gul et al (2020) The potential of the natural product diosmin as an antiviral agent targeting M pro has also been reported in several recent computational studies (Arun et al, 2020;Ngo et al, 2020;Peterson, 2020b;Peterson, 2020a). Chakraborti et al reported the potential of ruzasvir as a drug against SARS-CoV-2, although no data were provided (Chakraborti et al, 2020).…”

Section: Other Novel Putative Sars-cov-2 Drugs From the List Of 84 Drugsmentioning

confidence: 98%

Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

Piplani

Singh

Petrovsky

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

We urgently need to identify drugs to treat patients suffering from COVID-19 infection. Drugs rarely act at single molecular targets. Off-target effects are responsible for undesirable side effects and beneficial synergy between targets for specific illnesses. They have provided blockbuster drugs, e.g., Viagra for erectile dysfunction and Minoxidil for male pattern baldness. Existing drugs, those in clinical trials, and approved natural products constitute a rich resource of therapeutic agents that can be quickly repurposed, as they have already been assessed for safety in man. A key question is how to screen such compounds rapidly and efficiently for activity against new pandemic pathogens such as SARS-CoV-2. Here, we show how a fast and robust computational process can be used to screen large libraries of drugs and natural compounds to identify those that may inhibit the main protease of SARS-CoV-2. We show that the shortlist of 84 candidates with the strongest predicted binding affinities is highly enriched (≥25%) in compounds experimentally validated in vivo or in vitro to have activity in SARS-CoV-2. The top candidates also include drugs and natural products not previously identified as having COVID-19 activity, thereby providing leads for experimental validation. This predictive in silico screening pipeline will be valuable for repurposing existing drugs and discovering new drug candidates against other medically important pathogens relevant to future pandemics.

show abstract

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

Cited by 6 publications

References 114 publications

Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

Antiviral Effects of Some Flavonoids on SARS-CoV-2

Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

Contact Info

Product

Resources

About