Spontaneous binding of potential COVID-19 drugs (Camostat and Nafamostat) to human serine protease TMPRSS2.
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ABSTRACT:
SUBMITTER: Zhu H
PROVIDER: S-EPMC7809394 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC7844105 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral pathogen causing the coronavirus disease 2019 (COVID-19) global pandemic. No effective treatment for COVID-19 has been established yet. The serine protease transmembrane protease serine 2 (TMPRSS2) is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 into host cells. The protease inhibitor camostat, an anticoagulant used in the clinic, has potential anti-inflammatory and antiviral activities against COVID-19. However, the potential mechanisms of viral resistance and antiviral activity of camostat are unclear. Herein, we demonstrate high inhibitory potencies of camostat for a panel of serine proteases, indicating that camostat is a broad-spectrum inhibitor of serine proteases. In addition, we determined the crystal structure of camostat in complex with a serine protease (uPA [urokinase-type plasminogen activator]), which reveals that camostat is inserted in the S1 pocket of uPA but is hydrolyzed by uPA, and the cleaved camostat covalently binds to Ser195. We also generated a homology model of the structure of the TMPRSS2 serine protease domain. The model shows that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2, subsequently preventing SARS-CoV-2 spread. IMPORTANCE Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. The serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-CoV-2 entry into the host. Camostat mesylate (FOY 305), a serine protease inhibitor active against TMPRSS2 and used for the treatment of oral squamous cell carcinoma and chronic pancreatitis, inhibits SARS-CoV-2 infection of human lung cells. However, the direct inhibition mechanism of camostat mesylate for TMPRSS2 is unclear. Herein, we demonstrate that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2 as uPA, subsequently preventing SARS-CoV-2 spread.
| S-EPMC8428381 | biostudies-literature
Project description:SARS-CoV-2 uses the ACE2 receptor and the cellular protease TMPRSS2 for entry into target cells. The present study aimed to establish if the TMPRSS2 polymorphisms are associated with COVID-19 disease. The study included 609 patients with COVID-19 confirmed by RT-PCR test and 291 individuals negative for the SARS-CoV-2 infection confirmed by RT-PCR test and without antibodies anti-SARS-CoV-2. Four TMPRSS2 polymorphisms (rs12329760, rs2298659, rs456298, and rs462574) were determined using the 5'exonuclease TaqMan assays. Under different inheritance models, the rs2298659 (pcodominant2 = 0.018, precessive = 0.006, padditive = 0.019), rs456298 (pcodominant1 = 0.014, pcodominant2 = 0.004; pdominant = 0.009, precessive = 0.004, padditive = 0.0009), and rs462574 (pcodominant1 = 0.017, pcodominant2 = 0.004, pdominant = 0.041, precessive = 0.002, padditive = 0.003) polymorphisms were associated with high risk of developing COVID-19. Two risks (ATGC and GAAC) and two protectives (GAGC and GAGT) haplotypes were detected. High levels of lactic acid dehydrogenase (LDH) were observed in patients with the rs462574AA and rs456298TT genotypes (p = 0.005 and p = 0.020, respectively), whereas, high heart rate was present in patients with the rs462574AA genotype (p = 0.028). Our data suggest that the rs2298659, rs456298, and rs462574 polymorphisms independently and as haplotypes are associated with the risk of COVID-19. The rs456298 and rs462574 genotypes are related to high levels of LDH and heart rate.
| S-EPMC9505830 | biostudies-literature
Project description:The global coronavirus pandemic has burdened the human population with mass fatalities and disastrous socio-economic consequences. The frequent occurrence of these new variants has fueled the already prevailing challenge. There is still a necessity for highly effective small molecular agents to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we targeted the human transmembrane surface protease TMPRSS2, which is essential for proteolytic activation of SARS-CoV-2. Camostat is a well-known inhibitor of serine proteases and an effective TMPRSS2 inhibitor. A virtual library of camostat-like compounds was computationally screened against the catalytic site of TMPRSS2. Following a sequential in-depth molecular docking and dynamics simulation, we report the compounds that exhibited promising efficacy against TMPRSS2. The molecular docking and MM/PBSA free energy calculation study indicates these compounds carry excellent binding affinity against TMPRSS2 and found them more effective than camostat. The study will open doors for the effective treatment of coronavirus disease 2019.
| S-EPMC8787670 | biostudies-literature
Project description:UnlabelledThe human liver reacts to hepatitis C virus (HCV) with a balanced response consisting of host anti- and proviral activities. To explore these subtle host responses, we used oligonucleotide microarrays to investigate the differential gene expression between two groups of liver samples with high and low HCV loads (>100-fold difference). We identified and validated 26 genes that were up-regulated in livers with high HCV loads, including transmembrane protease serine 2 (TMPRSS2). Trypsin inhibitors inhibited the infection of Huh7-25-CD81 cells with cell-culture-derived HCV (HCVcc) of Japanese fulminant hepatitis 1 isolate at the postbinding and entry step, and trypsin enhanced HCVcc infection at an early stage of infection. Several major transmembrane serine proteases, in particular, furin and hepsin, were detected in Huh7-25-CD81 cells, but TMPRSS2 was not. Huh7-25-CD81 cell clones stably expressing TMPRSS2- WT (wild type) and inactive TMPRSS2-mutant genes showed positive and negative enhancement of their susceptibility to HCVcc infection, respectively. The enhanced susceptibility of TMPRSS2-WT Huh7-25-CD81 cells was confirmed by knockdown of TMPRSS2 using small interfering RNA. The cell-surface protease activity of TMPRSS2-WT cells was markedly active in the cleavage of QAR and QGR, corresponding to amino acid residues at P3 to P1.ConclusionThe cell-surface activity of a trypsin-like serine protease, such as TMPRSS2, activates HCV infection at the postbinding and entry stage. Host transmembrane serine proteases may be involved in the sensitivity, persistence, and pathogenesis of HCV infection and be possible targets for antiviral therapy.
| S-EPMC7165505 | biostudies-literature
Project description:A new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a respiratory infection out broke in December 2019 in Wuhan, Hubei province, China, resulted in pandemic conditions worldwide. COVID-19 spread swiftly around the world over with an alert of an emergency for an adequate drug. Therefore, in this research, we repurposed the FDA-approved medicines to find the prominent drug used to cure the COVID infected patients. We performed homology modeling of the transmembrane serine protease 2 (TMPRSS2), responsible for the viral entry. The prediction of the transmembrane region and the Conserved Domain in TMPRSS2 protein was made for docking. 4182 FDA-approved compounds from the ZINC database were downloaded and used for the calculation of physicochemical properties. Two thousand eight hundred fifteen screened compounds were used for molecular docking against the modelled protein structure. From which top hit compounds based on binding energy were extracted. At 1st site pose, ZINC3830554 showed the highest binding energy -12.91kcal/mol by forming Salt Bridge at LYS143, Hydrogen bond at ALA8, VAL45, HIS47, SER142, ASN277, ASN359, and TRP363. The hydrophobic Interactions at PHE3, LEU4, ALA7, ALA8, ALA139, PRO197, and PHE266. In the 2nd site pose, ZINC203686879 shows the highest binding energy (-12.56 kcal/mol) and forms a hydrophobic interaction with VAL187, VAL189, HIS205, LYS301, GLN347, TRP370 and hydrogen bond was at GLY300, THR302, GLN347, SER350 residues. These hit compounds were subjected to stability checks between the protein-ligand complex through the dynamics simulation (MD), and binding free energy was calculated through the Molecular Mechanics energies combined with Poisson-Boltzmann (MM/PBSA) method. We hope that hit compounds would be an efficient inhibitor that can block the TMPRSS2 activity and resist the entry of the SARS-CoV-2 virus into targeted human cells by reducing the virus's infectivity and transmissibility.
| S-EPMC7997164 | biostudies-literature
Project description:Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been responsible for the cause of global pandemic Covid-19 and to date, there is no effective treatment available. The spike 'S' protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design new drugs to control Covid-19. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell plays a significant role in the proteolytic cleavage of viral 'S' protein helpful for the priming of ACE2 receptors and viral entry into human cells. However, three-dimensional structural information and the inhibition mechanism of TMPRSS2 is yet to be explored experimentally. Hence, we have used a molecular dynamics (MD) simulated homology model of TMPRSS2 to study the inhibition mechanism of experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular modeling techniques. Prior to docking, all three inhibitors were geometry optimized by semi-empirical quantum chemical RM1 method. Molecular docking analysis revealed that Camostat mesylate and its structural analogue Nafamostat interact strongly with residues His296 and Ser441 present in the catalytic triad of TMPRSS2, whereas BHH binds with Ala386 along with other residues. Comparative molecular dynamics simulations revealed the stable behavior of all the docked complexes. MM-PBSA calculations also revealed the stronger binding of Camostat mesylate to TMPRSS2 active site residues as compared to Nafamostat and BHH. Thus, this structural information could be useful to understand the mechanistic approach of TMPRSS2 inhibition, which may be helpful to design new lead compounds to prevent the entry of SARS-Coronavirus 2 in human cells.
| S-EPMC8152215 | biostudies-literature
Project description:Transmembrane serine protease 2 is encoded by the TMPRSS2 gene. The gene is widely conserved and has two isoforms, both being autocatalytically activated from the inactive zymogen form. A fusion gene between the TMPRSS2 gene and ERG (erythroblast-specific-related gene), an oncogenic transcription factor, is the most common chromosomal aberration detected in prostate cancer, responsible for driving carcinogenesis. The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a diverse range of viruses. Both SARS-CoV and SARS-CoV-2 (COVID-19) use angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 to facilitate entry to cells, but with SARS-CoV-2 human-to-human transmission is much higher than SARS-CoV. As TMPRSS2 is expressed outside of the lung, and can therefore contribute to extrapulmonary spread of viruses, it warrants further exploration as a potential target for limiting viral spread and infectivity.
| S-EPMC7470178 | biostudies-literature
Project description:ObjectivesThe viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2.MethodsThis study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center.ResultsWe found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5' untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088).ConclusionsAmong individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.
| S-EPMC8102075 | biostudies-literature
Project description:The type II transmembrane serine protease TMPRSS2 facilitates the entry of coronaviruses, such as SARS-CoV-2, into host cells by cleaving the S1/S2 interface of the viral spike protein. Based on structural data derived from X-ray crystallographic data of related trypsin-like proteases, a homology model of TMPRSS2 is described and validated using the broad spectrum COVID-19 drug candidate camostat as a probe. Both active site recognition and catalytic function are examined using quantum mechanics/molecular mechanics molecular dynamic (QM/MM MD) simulations of camostat and its active metabolite, 4-(4-guanidinobenzoyloxy) phenylacetate (GBPA). Substrate binding is shown to be primarily stabilized through salt bridge formation between the shared guanidino pharmacophore and D435 in pocket A (flanking the catalytic S441). Based on the binding mode of GBPA, residues K342 and W461 have been identified as potential contacts involved in TMPRSS2 selective binding and activity. Additional data is reported that indicates the transition state structure is stabilized through H-bonding interactions with the backbone N-H groups within an oxyanion hole following bottom-side attack of the carbonyl by S441. This is supported by prior work on related serine proteases suggesting further strategies to exploit in the design of more potent inhibitors. Taken overall, the proposed structure along with the key contact sites and mechanistic features identified should prove highly advantageous to the design and rational development of safe and effective therapeutics that target TMPRSS2 and avoid inhibition of other trypsin-dependent processes.
| S-EPMC7862521 | biostudies-literature