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.
Background - High-molecular weight heparin (HMWH), a molecule which is extensively in use as an anticoagulant shows concentration-dependent angiogenic and anti-angiogenic potential. Based on the concentration, HMWH can bind with both angiogenic and anti-angiogenic factors and exerts diverse effect. Our earlier data suggested that HMWH (15 kDa) can induce concentration-dependent neovascularization on chicken chorioallantoic membrane (CAM). The diffusion pattern of HMWH through various layers of CAM supports its internalized action with the various cellular components of angiogenesis. So far, no studies have reported the interactive potential of HMWH with various pro-angiogenic growth factors under physiological conditions. Hence, we aimed to find the transcription level interaction of HMWH with major pro-angiogenic growth factors. In connection to the research, for the first time, we validated the three-dimensional structures of chicken-specific pro-angiogenic growth factors such as FGF2, MMP2, MMP9, NOS3, VEGF A, and VEGF C to find the binding affinity of HMWH with the core-functional units of these growth factors. Methods - CAMs are incubated with 50, 100, and 150 µM concentration of HMWH. Changes in the transcription level of specified pro-angiogenic growth factors are analyzed by semi-PCR method. The functional aspects of these molecules are identified with zymogram and immunohistochemical approaches. Scanning electron microscopic technique is applied to find the morphological changes on CAM under HMWH incubation. Three-dimensional structure validation and molecular docking are performed using the SWISS-MODEL web server and AutoDock vina-PyRx software version 8.0. Results - HMWH can enhance the transcription level of major pro-angiogenic growth factors with a significant impact on FGF2 and MMP2 under 100 µM concentration. The in-silico analysis reveals that HMWH shows a higher binding affinity with FGF2 followed by MMP2, MMP9, NOS3, VEGF A, and VEGF C, respectively. Conclusion - The combined results from the experimental and in-silico analysis reveal that HMWH can interact with pro-angiogenic growth factors under micromolar concentration in physiological conditions while inducing angiogenesis. This observation further supports the therapeutic benefits of HMWH as an angiogenic factor under micromolar concentration.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.