scholarly journals A new virtual screening approach for protein disulfide isomerase inhibitors reveals potential candidates for antithrombotic agents

2016 ◽  
Author(s):  
Noureddine Ben Khalaf ◽  
Moiz Bakhiet
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Arterial Thrombosis ◽  
Protein Disulfide Isomerase ◽  
Dynamics Simulation ◽  
Autodock Vina ◽  
Disulfide Isomerase ◽  
Protein Disulfide

Background: Arterial thrombosis causes heart attacks and strokes and constitutes one of the leading causes of morbidity and mortality in the world and few therapies are available for its treatment. Thus, new therapeutic approaches in the prevention and treatment of arterial thrombosis are needed. Protein disulfide isomerase (PDI) has been shown to be expressed on vascular cells following injury and to be involved in regulating thrombus formation in vivo. Since inhibition of PDI prevents platelet accumulation and fibrin generation, it makes it a valuable target for the development of new antithrombotics. Rutin, a flavonol glycoside derivative of Quercetin, was previously described for displaying decent potency against PDI, and it inhibited the agonist-induced platelets aggregation in vivo, however its utility is limited by its low solubility and its off-target activity. Rutin was recently reported to bind specifically to the b’ domain of PDI affecting protein flexibility which results in the inhibition of its reductase activity. To investigate Rutin inhibitory mechanism we used docking and molecular dynamics simulation and we observed that Rutin binds to a specific hydrophobic pocket of the b’ domain which reduces PDI flexibility. Methods: In an attempt to identify more potent, soluble and specific PDI inhibitors, we established an in silico approach based on similarity search in Zinc Drug-like library composed of more than 17 million compounds satisfying Lipiniski’s rule of five. A KNIME workflow was established for selecting Rutin-similar compounds based on Tanimoto coefficients. Then, a virtual screening of selected compounds was performed using Autodock Vina on PDI target pocket. In order to select PDI specific probes, a counter-screen was run to eliminate hits binding Erp57 thioredoxin active site. Hits were then submitted to druglikeness prediction using Quantitative Estimate of Druglikeness (QED). A total of 5 compounds were selected and submitted to re-docking with Autodock Vina. Complexes were subject to Molecular Dynamics simulation using NAMD. Results and Discussion: a total of 4 compounds were shown to form stable complexes with PDI binding pocket and then could constitute promising candidates for lead optimization. In conclusion, our in silico approach lead to the identification of potential novel PDI inhibitors that may form suitable candidates for Arterial thrombosis drug discovery.

scholarly journals A new virtual screening approach for protein disulfide isomerase inhibitors reveals potential candidates for antithrombotic agents

2016 ◽  
Author(s):  
Noureddine Ben Khalaf ◽  
Moiz Bakhiet
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Arterial Thrombosis ◽  
Protein Disulfide Isomerase ◽  
Dynamics Simulation ◽  
Autodock Vina ◽  
Disulfide Isomerase ◽  
Protein Disulfide

Background: Arterial thrombosis causes heart attacks and strokes and constitutes one of the leading causes of morbidity and mortality in the world and few therapies are available for its treatment. Thus, new therapeutic approaches in the prevention and treatment of arterial thrombosis are needed. Protein disulfide isomerase (PDI) has been shown to be expressed on vascular cells following injury and to be involved in regulating thrombus formation in vivo. Since inhibition of PDI prevents platelet accumulation and fibrin generation, it makes it a valuable target for the development of new antithrombotics. Rutin, a flavonol glycoside derivative of Quercetin, was previously described for displaying decent potency against PDI, and it inhibited the agonist-induced platelets aggregation in vivo, however its utility is limited by its low solubility and its off-target activity. Rutin was recently reported to bind specifically to the b’ domain of PDI affecting protein flexibility which results in the inhibition of its reductase activity. To investigate Rutin inhibitory mechanism we used docking and molecular dynamics simulation and we observed that Rutin binds to a specific hydrophobic pocket of the b’ domain which reduces PDI flexibility. Methods: In an attempt to identify more potent, soluble and specific PDI inhibitors, we established an in silico approach based on similarity search in Zinc Drug-like library composed of more than 17 million compounds satisfying Lipiniski’s rule of five. A KNIME workflow was established for selecting Rutin-similar compounds based on Tanimoto coefficients. Then, a virtual screening of selected compounds was performed using Autodock Vina on PDI target pocket. In order to select PDI specific probes, a counter-screen was run to eliminate hits binding Erp57 thioredoxin active site. Hits were then submitted to druglikeness prediction using Quantitative Estimate of Druglikeness (QED). A total of 5 compounds were selected and submitted to re-docking with Autodock Vina. Complexes were subject to Molecular Dynamics simulation using NAMD. Results and Discussion: a total of 4 compounds were shown to form stable complexes with PDI binding pocket and then could constitute promising candidates for lead optimization. In conclusion, our in silico approach lead to the identification of potential novel PDI inhibitors that may form suitable candidates for Arterial thrombosis drug discovery.

Abstract 806: Protein Disulfide Isomerase (PDI) signals Tissue Factor (TF)-dependent Fibrin formation in vivo

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Marie-Luise von Bruehl ◽  
Lenka Grahl ◽  
Ildiko Konrad ◽  
Michael Lorenz ◽  
Christian Schulz ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Arterial Thrombosis ◽  
Protein Disulfide Isomerase ◽  
Disulfide Isomerase ◽  
Intravascular Coagulation ◽  
Disulfide Formation ◽  
Fibrin Formation ◽  
Protein Disulfide

Background: Pathological fibrin formation is a predominant cause for arterial thrombosis, triggering myocardial infarction and stroke. Tissue factor (TF), which is expressed by vascular endothelium and cell-derived microparticles, is a central trigger of intravascular fibrin generation. In intact blood vessels, TF is only minimally active, and the coagulation system is down-regulated. In contrast, TF is rapidly stimulated following endothelial disruption. However, the molecular mechanisms that trigger fibrin formation via regulation of TF activation are largely undefined. Methods and Results: Here, we have identified a novel pathway that leads to TF activation in vitro and contributes to intravascular coagulation in vivo. We show that the protein disulfide isomerase (PDI) induces disulfide formation of the Cys186/Cys209 pair located in the extracellular domain of TF. In vitro, PDI-mediated disulfide formation led to profound activation of TF. In vivo, we found that PDI is not present in the intact vessel wall, but becomes abundantly expressed following vessel damage. We show that injured smooth muscle cells and adherent/activated platelets are the major cellular sources of PDI at sites of vascular injury. We then assessed fibrin formation following injury of the common carotid artery using intravital microscopy. We observed that PDI-blockade strongly reduced fibrin formation by approximately 45– 60%. Likewise, intravenous infusion of PDI significantly enhanced TF-dependent fibrin formation. Together, this implies that PDI initiates coagulation in vitro and also during arterial thrombosis in vivo. Notably, PDI did not act on platelets to trigger intravascular coagulation. Correspondingly, PDI blockade also inhibited fibrin formation, when platelet adhesion was prevented using a function-blocking anti-GPVI antibody. Conclusion: These findings reveal for the first time in vivo that the thiol isomerase PDI is a major molecular trigger of blood coagulation, which is exposed after vessel injury and converts TF into its functionally active form. Hence, PDI represents a promising novel target for the treatment of pathologic fibrin formation in patients with thrombotic disorders.

scholarly journals An Analysis Based on Molecular Docking and Molecular Dynamics Simulation Study of Bromelain as Anti-SARS-CoV-2 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Trina Ekawati Tallei ◽  
Fatimawali ◽  
Afriza Yelnetty ◽  
Rinaldi Idroes ◽  
Diah Kusumawaty ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Three Dimensional ◽  
Md Simulations ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Novel Coronavirus

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, more in vitro and in vivo research on this potential mechanism of action is required.

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