Molecular Insights into Human Transmembrane Protease Serine-2 (TMPS2) Inhibitors against SARS-CoV2: Homology Modelling, Molecular Dynamics, and Docking Studies

Kishk, Safaa M.; El‐Fadeal, Noha M. Abd; Yassen, Asmaa S. A.; Nafie, Mohamed S.; Nemr, Nader; ElMasry, Gamal; Al‐Rejaie, Salim S.; Simons, Claire

doi:10.3390/molecules25215007

Cited by 29 publications

(20 citation statements)

References 39 publications

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“…It was discovered that GBPA, the active metabolite of camostat mesilate, inhibits TMPRSS2 and prevents SARS-CoV-2 infection of human airway cells. [6][7][8][9][10][11][12][13] Furthermore, a smallscale retrospective study suggested a potential therapeutic effect of camostat mesilate in patients admitted to an intensive care unit. 21 Despite promising results of preclinical studies, as well as a small retrospective study, the results of our study indicate that camostat mesilate is no more effective than placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms.…”

Section: Discussionmentioning

confidence: 99%

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Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

Kinoshita

Shinoda

Nisizaki

et al. 2022

Preprint

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Background: In vitro drug-screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). Methods: This was a phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. Findings: One-hundred and fifty-five patients were randomised to receive camostat mesilate (n=78) or placebo (n=77). The median time to the first test was 11 days in both groups, and conversion to negative status was observed in 60.8% and 63.5% of patients in the camostat mesilate and placebo groups, respectively. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. Interpretation: Camostat mesilate is no more effective, based on upper airway viral clearance, than placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. Funding: Ono Pharmaceutical Co., Ltd.

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Section: Discussionmentioning

confidence: 99%

“…In vitro drug-screening studies have indicated that 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA), the active metabolite of the serine protease inhibitor camostat mesilate (FOY-305), inhibits TMPRSS2 and prevents SARS-CoV-2 infection of a human airway epithelial cell-derived cell line (Calu-3 cells). 6–13…”

Section: Introductionmentioning

confidence: 99%

Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

Kinoshita

Shinoda

Nisizaki

et al. 2022

Preprint

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“…The 3D structure of TMPRSS2 was obtained from Brookhaven protein databank (PDB ID: 7 MEQ) [ 12 ]. The TMPRSS2 FASTA sequence (accession number: O15393) was extracted from the UniProt database and modelled with Swiss model server using the crystal structure (PDB ID: 7MEQ) as a template because of the presence of some missing loop regions in the resolved crystal structure [ 13 ].…”

Section: Methodsmentioning

confidence: 99%

Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein

et al. 2022

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Background The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules. Results Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( − 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( − 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( − 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket. Conclusion The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.

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“…Kishk et al identified proteins with known X-ray structure and high homology for TMPRSS2 using SWISS-MODEL and NCBI blastp [ 102 ]. These proteins included transmembrane protease serine 1 and 13 and a group of human plasma kallikrein.…”

Section: Molecular Modeling Studiesmentioning

confidence: 99%

The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19

Mantzourani

Vasilakaki

Gerogianni

et al. 2022

Expert Opinion on Drug Discovery

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Introduction Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the devastating pandemic named coronavirus disease 2019 (COVID-19). Unfortunately, the discovery of antiviral agents to combat COVID-19 is still an unmet need. Transmembrane serine protease 2 (TMPRSS2) is an important mediator in viral infection and thus, TMPRRS2 inhibitors may be attractive agents for COVID-19 treatment. Areas covered This review article discusses the role of TMPRSS2 in SARS-CoV-2 cell entry and summarizes the inhibitors of TMPRSS2 and their potential anti-SARS activity. Two known TMPRSS2 inhibitors, namely camostat and nafamostat, approved drugs for the treatment of pancreatitis, are under clinical trials as potential drugs against COVID-19. Expert opinion Due to the lack of the crystal structure of TMPRSS2, homology models have been developed to study the interactions of known inhibitors, including repurposed drugs, with the enzyme. However, novel TMPRSS2 inhibitors have been identified through high-throughput screening, and appropriate assays studying their in vitro activity have been set up. The discovery of TMPRSS2ʹs crystal structure will facilitate the rational design of novel inhibitors and in vivo studies and clinical trials will give a clear answer if TMPRSS2 inhibitors could be a new weapon against COVID-19.

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Molecular Insights into Human Transmembrane Protease Serine-2 (TMPS2) Inhibitors against SARS-CoV2: Homology Modelling, Molecular Dynamics, and Docking Studies

Cited by 29 publications

References 39 publications

Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein

The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19

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