Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2

Sonawane, Kailas D.; S, Barale Sagar; J, Dhanavade Maruti; R, Waghmare Shailesh; H, Nadaf Naiem; Kamble, Subodh A.; Abdulmawjood, Mohammed Ali; M, Makandar Asiya; M, Fandilolu Prayagraj; S, Dound Ambika; Naik, Nitin M.

doi:10.26434/chemrxiv.12162360.v1

Cited by 30 publications

(18 citation statements)

References 26 publications

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“…Structural insights into the interactions of the three inhibitors described above with TMPRSS2 have been reported via computational study [ 134 ]. The molecular docking analysis revealed that camostat and nafamostat interact directly with residues His296, Asp435, and Ser441 in the catalytic domain of TMPRSS2.…”

Section: Potential Small Molecule Inhibitors Of Early Viral Eventsmentioning

confidence: 99%

Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials

Al‐Horani

Kar

Aliter

2020

IJMS

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The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.

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Section: Potential Small Molecule Inhibitors Of Early Viral Eventsmentioning

confidence: 99%

Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials

Al‐Horani

Kar

Aliter

2020

IJMS

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“…To understand the binding affinity and the intermolecular interaction of the chosen three drug molecules camostat, nafamostat, and leupeptin [16,[18][19][20] (https://clinicaltrials.gov/ct2/show/ NCT04353284) with the active site amino acids of TMPRSS2, the molecular docking simulation was performed. In prior to the docking simulation, the abovesaid three drug molecules were prepared by the Ligprep module of Schrödinger software [28].…”

Section: Preparation Of Ligands and Receptor For Dockingmentioning

confidence: 99%

“…Camostat mesylate, nafamostat, and leupeptin (Fig. 1) are the drugs chosen as the inhibitors of TMPRSS2, in which the drugs camostat and nafamostat are under clinical trial for COVID-19 [13,16,[18][19][20] (https://clinicaltrials.gov/ct2/show/NCT04353284) treatment, whereas leupeptin [21] is tested for its suitability against SARS-CoV-2 viral infection and also studied for its antiviral properties against SARS-CoV viruses [22,23]. To better understand the molecular binding mechanisms of these molecules, which are not completely known at the molecular dynamics level, we have computed the binding affinity, intermolecular interactions, and the stability of molecules from the molecular docking and the molecular dynamics simulations.…”

Section: Introductionmentioning

confidence: 99%

Strong Binding of Leupeptin with TMPRSS2 Protease May Be an Alternative to Camostat and Nafamostat for SARS-CoV-2 Repurposed Drug: Evaluation from Molecular Docking and Molecular Dynamics Simulations

Ramakrishnan

Kandasamy

Iruthayaraj

et al. 2021

Appl Biochem Biotechnol

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The unprecedented coronavirus SARS-CoV-2 outbreak at Wuhan, China, caused acute respiratory infection to humans. There is no precise vaccine/therapeutic agents available to combat the COVID-19 disease. Some repurposed drugs are saving the life of diseased, but the complete cure is relatively less. Several drug targets have been reported to inhibit the SARS-CoV-2 virus infection, in that TMPRSS2 (transmembrane protease serine 2) is one of the potential targets; inhibiting this protease stops the virus entry into the host human cell. Camostat mesylate, nafamostat, and leupeptin are the drugs, in which the first two drugs are being used for COVID-19 and leupeptin also tested. To consider these drugs as the repurposed drug for COVID-19, it is essential to understand their binding affinity and stability with TMPRSS2. In the present study, we performed the molecular docking and molecular dynamics (MD) simulation of these molecules with the TMPRSS2. The docking study reveals that leupeptin molecule strongly binds with TMPRSS2 protein than the other two drug molecules. The RMSD and RMSF values of MD simulation confirm that leupeptin and the amino acids of TMPRSS2 are very stable than the other two molecules. Furthermore, leupeptin forms interactions with the key amino acids of TMPRSS2 and the same have been maintained during the MD simulations. This structural and dynamical information is useful to evaluate these drugs to be used as repurposed drugs, however, the strong binding profile of leupeptin with TMPRSS2, suggests, it may be considered as a repurposed drug for COVID-19 disease after clinical trial.

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“…Although the structure of human TMPRSS2 is not available yet, homology modeling and in silico docking studies have demonstrated the molecular mechanisms of camostat mesylate, nafamostat, and bromhexine hydrochloride in inhibiting TMPRSS2 (Sonawane et al, 2020 ). In this respect, active site-specific inhibitors of TMPRSS2 can be used as potential antiviral agents against SARS-CoV-2.…”

Section: Antiviral Strategies Against Sars-cov-2mentioning

confidence: 99%

Therapeutic Strategies Against COVID-19 and Structural Characterization of SARS-CoV-2: A Review

et al. 2020

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The novel coronavirus, SARS-CoV-2, or 2019-nCoV, which originated in Wuhan, Hubei province, China in December 2019, is a grave threat to public health worldwide. A total of 3,672,238 confirmed cases of coronavirus disease 2019 (COVID-19) and 254,045 deaths were reported globally up to May 7, 2020. However, approved antiviral agents for the treatment of patients with COVID-19 remain unavailable. Drug repurposing of approved antivirals against other viruses such as HIV or Ebola virus is one of the most practical strategies to develop effective antiviral agents against SARS-CoV-2. A combination of repurposed drugs can improve the efficacy of treatment, and structure-based drug design can be employed to specifically target SARS-CoV-2. This review discusses therapeutic strategies using promising antiviral agents against SARS-CoV-2. In addition, structural characterization of potentially therapeutic viral or host cellular targets associated with COVID-19 have been discussed to refine structure-based drug design strategies.

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Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2

Cited by 30 publications

References 26 publications

Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials

Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials

Strong Binding of Leupeptin with TMPRSS2 Protease May Be an Alternative to Camostat and Nafamostat for SARS-CoV-2 Repurposed Drug: Evaluation from Molecular Docking and Molecular Dynamics Simulations

Therapeutic Strategies Against COVID-19 and Structural Characterization of SARS-CoV-2: A Review

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