Discovery of novel potential inhibitors of TMPRSS2 and Mpro of SARS‐CoV‐2 using E-pharmacophore and docking-based virtual screening combined with molecular dynamic and quantum mechanics

Mahgoub, Mohanad A.; Alnaem, Ahmed; Fadlelmola, Mohammed; Abo-idris, Mazin; Makki, Alaa A.; Abdelgadir, Abdelgadir A.; Alzain, Abdulrahim A.

doi:10.1080/07391102.2022.2112080

Cited by 5 publications

(4 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Then, they carried out MM-GBSA and predictive ADMET, and the QM-optimised structures of the most promising hits were found to optimally bind to both active sites. Further MD simulations indicated the potential of three compounds (i.e., Z751959696, Z751954014 and Z56784282) as dual-action inhibitors with adequate pharmacokinetic profile [ 123 ].…”

Section: Dual-action Inhibitorsmentioning

confidence: 99%

A Tale of Two Proteases: MPro and TMPRSS2 as Targets for COVID-19 Therapies

Farkaš,

Minneci,

Misevicius

et al. 2023

Pharmaceuticals

View full text Add to dashboard Cite

Considering the importance of the 2019 outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in the coronavirus disease 2019 (COVID-19) pandemic, an overview of two proteases that play an important role in the infection by SARS-CoV-2, the main protease of SARS-CoV-2 (MPro) and the host transmembrane protease serine 2 (TMPRSS2), is presented in this review. After summarising the viral replication cycle to identify the relevance of these proteases, the therapeutic agents already approved are presented. Then, this review discusses some of the most recently reported inhibitors first for the viral MPro and next for the host TMPRSS2 explaining the mechanism of action of each protease. Afterward, some computational approaches to design novel MPro and TMPRSS2 inhibitors are presented, also describing the corresponding crystallographic structures reported so far. Finally, a brief discussion on a few reports found some dual-action inhibitors for both proteases is given. This review provides an overview of two proteases of different origins (viral and human host) that have become important targets for the development of antiviral agents to treat COVID-19.

show abstract

Section: Dual-action Inhibitorsmentioning

confidence: 99%

A Tale of Two Proteases: MPro and TMPRSS2 as Targets for COVID-19 Therapies

Farkaš,

Minneci,

Misevicius

et al. 2023

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…Numerous TMPRSS2 inhibitors have been tested in in vitro studies that showed they inhibit entry of SARS-CoV-2 in lung cells, including notably camostat, nafamostat and several peptidomimetic inhibitors [67,[106][107][108][109]. These inhibitors were either 'repurposed' commercially available drugs, designed de novo or identified by virtual screenings and have been reviewed extensively elsewhere [110][111][112][113][114][115]. Several of these compounds have already been or are currently being investigated in randomised, controlled trials to assess their use as monotherapies against COVID-19.…”

Section: Ace2 and Tmprss2 As Candidate Targets For Antiviral Therapymentioning

confidence: 99%

Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients

Giotis

Cil

Brooke

2022

Viruses

View full text Add to dashboard Cite

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), is estimated to have caused over 6.5 million deaths worldwide. The emergence of fast-evolving SARS-CoV-2 variants of concern alongside increased transmissibility and/or virulence, as well as immune and vaccine escape capabilities, highlight the urgent need for more effective antivirals to combat the disease in the long run along with regularly updated vaccine boosters. One of the early risk factors identified during the COVID-19 pandemic was that men are more likely to become infected by the virus, more likely to develop severe disease and exhibit a higher likelihood of hospitalisation and mortality rates compared to women. An association exists between SARS-CoV-2 infectiveness and disease severity with sex steroid hormones and, in particular, androgens. Several studies underlined the importance of the androgen-mediated regulation of the host protease TMPRSS2 and the cell entry protein ACE2, as well as the key role of these factors in the entry of the virus into target cells. In this context, modulating androgen signalling is a promising strategy to block viral infection, and antiandrogens could be used as a preventative measure at the pre- or early hospitalisation stage of COVID-19 disease. Different antiandrogens, including commercial drugs used to treat metastatic castration-sensitive prostate cancer and other conditions, have been tested as antivirals with varying success. In this review, we summarise the most recent updates concerning the use of antiandrogens as prophylactic and therapeutic options for COVID-19.

show abstract

“…Numerous TMPRSS2 inhibitors have been tested in in vitro studies that showed they inhibit entry of SARS-CoV-2 in lung cells including notably camostat, nafamostat, and several peptidomimetic inhibitors [63,[100][101][102][103]. These inhibitors were either 'repurposed' commercially available drugs, designed de novo or identified by virtual screenings and have been reviewed extensively elsewhere [104][105][106][107][108][109]. Several of these compounds have already or are currently been investigated in randomized, controlled trials to assess their use as monotherapies against COVID-19.…”

Section: Ace2 and Tmprss2 As Candidate Targets For Antiviral Therapymentioning

confidence: 99%

Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients

Giotis¹,

Cil²,

Brooke³

2022

Preprint

View full text Add to dashboard Cite

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), is estimated to have caused over 6.5 million deaths to date worldwide. The emergence of fast-evolving SARS-CoV-2 variants of concern alongside increased transmissibility and/or virulence as well as immune and vaccine escape capabilities highlight the urgent need for more effective antivirals to combat the disease in the long run along with regularly updated vaccine boosters. One of the early risk factors identified during the COVID-19 pandemic was that men are more likely to get infected by the virus, more likely to develop severe disease and exhibit higher likelihood of hospitalisation and mortality rates compared to women. An association exists between SARS-CoV-2 infectiveness and disease severity with sex steroid hormones and in particular androgens. Several studies underlined the importance of the androgen-mediated regulation of the host protease TMPRSS2 and the cell entry protein ACE2 as well as the key role of these factors in the entry of the virus into target cells. In this context, modulating androgen signalling is a promising strategy to block viral infection and antiandrogens could be used as a preventative measure at the pre- or early-hospitalisation stage of COVID-19 disease. Different antiandrogens, including commercial drugs used to treat metastatic castration-sensitive prostate cancer and other conditions, have been tested as antivirals with varying success. In this review, we summarise the most recent updates concerning the use of antiandrogens as prophylactic and therapeutic options for COVID-19.

show abstract

Discovery of novel potential inhibitors of TMPRSS2 and Mpro of SARS‐CoV‐2 using E-pharmacophore and docking-based virtual screening combined with molecular dynamic and quantum mechanics

Cited by 5 publications

References 43 publications

A Tale of Two Proteases: MPro and TMPRSS2 as Targets for COVID-19 Therapies

A Tale of Two Proteases: MPro and TMPRSS2 as Targets for COVID-19 Therapies

Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients

Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients

Contact Info

Product

Resources

About