scholarly journals Evaluation of Xa inhibitors as potential inhibitors of the SARS-CoV-2 Mpro protease

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262482
Author(s):  
Katarzyna Papaj ◽  
Patrycja Spychalska ◽  
Patryk Kapica ◽  
André Fischer ◽  
Jakub Nowak ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Therapeutic Effect ◽  
In Silico ◽  
Large Scale ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Microscale Thermophoresis ◽  
Potential Inhibitors

Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 Mpro. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 Mpro with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 Mpro inhibition is rather negligible.

In silico Assessment of Factor Xa Inhibitors by Docking Studies

2013 ◽  
Vol 1 (1) ◽  
pp. 9 ◽  
Author(s):  
Syed Mohamed Abubacker ◽  
Akkiraju Pavanchand ◽  
Siddique Babu Basheer ◽  
Konereddy Sriveena ◽  
Rachel Paul ◽  
...  
Keyword(s):  
In Silico ◽  
Factor Xa ◽  
Docking Studies ◽  
Factor Xa Inhibitors

Anticoagulant activity screening of an in-house database of natural compounds for discovering novel selective factor Xa inhibitors; a combined in silico and in vitro approach

2020 ◽  
Vol 29 (4) ◽  
pp. 707-726
Author(s):  
Reham S. Ibrahim ◽  
Rahma SR. Mahrous ◽  
Hoda M. Fathy ◽  
Abdallah A. Omar ◽  
Rasha M. Abu EL-Khair
Keyword(s):  
In Silico ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Natural Compounds ◽  
Factor Xa Inhibitors ◽  
Activity Screening

Synthetic Anti-Xa Drugs Can Be Used for Parenteral Anticoagulation but Not Fondaparinux.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4088-4088
Author(s):  
Omer Iqbal ◽  
Debra Hoppensteadt ◽  
Daniel Fareed ◽  
Jawed Fareed
Keyword(s):  
Large Scale ◽  
Factor Xa ◽  
The United States ◽  
Final Concentration ◽  
Anticoagulant Effect ◽  
Factor Xa Inhibitors ◽  
Vein Thrombosis ◽  
Prothrombinase Complex ◽  
United States Food ◽  
Important Approach

Abstract Targeting at the level of factor Xa and/or prothrombinase complex by synthetic anti-Xa agents such as JTV-803 (Akros Pharma, Princeton, NJ), DX-9065a (Daiichi Pharmaceuticals, Tokyo, Japan), and Fondaparinux (Sanofi-Synthelabo, Toulouse, France) represents an important approach in anticoagulant therapy. Factor Xa is an essential component of the prothrombinase complex and leads to the generation of thrombin. Synthetic heparin pentasaccharide, Fondaparinux (Arixtra®) has been approved by the United States Food and Drug Administration for the prophylaxis of deep vein thrombosis in patients undergoing hip and knee replacement surgeries. There is a rapid stride in the development of newer synthetic inhibitors of factor Xa such as DX-9065a, and JTV-803 in various thrombotic indications. In order to evaluate the parenteral anticoagulant potential of these synthetic factor Xa inhibitors, we used the Hemochron (celite) activated clotting time (ACT) assay. DX-9065a at a final concentration of 5 and 10 μg/ml increased the ACTs to 250 and 300 seconds, respectively. Similar anticoagulant potential was noticed with JTV-803. These findings suggest that these agents may be useful as parenteral anticoagulants during interventional cardiologic procedures, surgical anticoagulation and for the prevention of vascular access occlusion. Fondaparinux requiring antithrombin (AT) for its anticoagulant effect does not increase the celite ACT to the extent as other synthetic factor Xa inhibitors. Fondaparinux even at a final concentration of 100 μg/ml increase the ACT to about 200 seconds and hence are not suitable to be used as parenteral anticoagulants. The concentrations of JTV-803, DX-9065a and fondaparinux required to increase the ACT to near 250 seconds are 6.2, 5 and 125 μg/ml, respectively. While fondaparinux is AT-dependent, the synthetic anti-Xa agents are AT-independent in their actions. The antithrombin sparing effect of direct anti-Xa agents may contribute to an additional anticoagulant effect as reflected by increased ACT levels. Furthermore, there are some other advantages of direct anti-Xa agents when compared to fondaparinux. While direct anti-Xa agents may be used for patients with AT deficiency, fondaparinux being AT-dependent, may not. The inhibition of the clot-bound and prothrombinase-bound factor Xa are additional advantages of direct Xa inhibitors when compared to fondaparinux. Fondaparinux being AT-dependent and upon complexation with AT is not capable of inhibiting the clot-bound factor Xa. Oral Xa inhibitors are being developed and when available patients may have an ideal transition from a parenteral anti-Xa agent to an oral Xa inhibitor. The results clearly suggest that synthetic factor Xa inhibitors except fondaparinux may be used as parenteral anticoagulants. Large-scale clinical studies are warranted to evaluate these findings.

In Silico Inhibition of BACE-1 by Selective Phytochemicals as Novel Potential Inhibitors: Molecular Docking and DFT Studies

2020 ◽  
Vol 17 (3) ◽  
pp. 397-411 ◽  
Author(s):  
Nadia Arif ◽  
Andleeb Subhani ◽  
Waqar Hussain ◽  
Nouman Rasool
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
In Silico ◽  
Density Functional ◽  
Energy Gap ◽  
Human Beings ◽  
Potential Inhibitors ◽  
Bace 1

Background: Alzheimer’s Disease (AD) has become the most common age-dependent disease of dementia. The trademark pathologies of AD are the presence of amyloid aggregates in neurofibrils. Recently phytochemicals being considered as potential inhibitors against various neurodegenerative, antifungal, antibacterial and antiviral diseases in human beings. Objective: This study targets the inhibition of BACE-1 by phytochemicals using in silico drug discovery analysis. Methods: A total of 3150 phytochemicals were collected from almost 25 different plants through literature assessment. The ADMET studies, molecular docking and density functional theory (DFT) based analysis were performed to analyze the potential inhibitory properties of these phytochemicals. Results: The ADMET and docking results exposed seven compounds that have high potential as an inhibitory agent against BACE-1 and show binding affinity >8.0 kcal/mol against BACE-1. They show binding affinity greater than those of various previously reported inhibitors of BACE-1. Furthermore, DFT based analysis has shown high reactivity for these seven phytochemicals in the binding pocket of BACE- 1, based on ELUMO, EHOMO and Kohn-Sham energy gap. All seven phytochemicals were testified (as compared to experimental ones) as novel inhibitors against BACE-1. Conclusion: Out of seven phytochemicals, four were obtained from plant Glycyrrhiza glabra i.e. Shinflavanone, Glabrolide, Glabrol and PrenyllicoflavoneA, one from Huperzia serrate i.e. Macleanine, one from Uncaria rhynchophylla i.e. 3a-dihydro-cadambine and another one was from VolvalerelactoneB from plant Valeriana-officinalis. It is concluded that these phytochemicals are suitable candidates for drug/inhibitor against BACE-1, and can be administered to humans after experimental validation through in vitro and in vivo trials.

scholarly journals Biologically guided isolation and ADMET profile of new factor Xa inhibitors from Glycyrrhiza glabra roots using in vitro and in silico approaches

RSC Advances ◽  
2021 ◽  
Vol 11 (17) ◽  
pp. 9995-10001
Author(s):  
Reham S. Ibrahim ◽  
Rahma S. R. Mahrous ◽  
Rasha M. Abu EL-Khair ◽  
Samir A. Ross ◽  
Abdallah A. Omar ◽  
...  
Keyword(s):  
In Silico ◽  
Factor Xa ◽  
Glycyrrhiza Glabra ◽  
Factor Xa Inhibitors

Biologically guided isolation of new factor Xa inhibitors from Glycyrrhiza glabra roots.

Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors

1990 ◽  
Vol 63 (02) ◽  
pp. 220-223 ◽  
Author(s):  
J Hauptmann ◽  
B Kaiser ◽  
G Nowak ◽  
J Stürzebecher ◽  
F Markwardt
Keyword(s):  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Factor Xa Inhibitors ◽  
Venous Stasis ◽  
Clotting Time ◽  
Thrombosis Model ◽  
Activity Factor ◽  
Antithrombotic Effects

SummaryThe anticoagulant effect of selected synthetic inhibitors of thrombin and factor Xa was studied in vitro in commonly used clotting assays. The concentrations of the compounds doubling the clotting time in the various assays were mainly dependent on their thrombin inhibitory activity. Factor Xa inhibitors were somewhat more effective in prolonging the prothrombin time compared to the activated partial thromboplastin time, whereas the opposite was true of thrombin inhibitors.In vivo, in a venous stasis thrombosis model and a thromboplastin-induced microthrombosis model in rats the thrombin inhibitors were effective antithrombotically whereas factor Xa inhibitors of numerically similar IQ value for the respective enzyme were not effective at equimolar dosageThe results are discussed in the light of the different prelequisiles and conditions for inhibition of thrombin and factor Xa in the course of blood clotting.

Machine Learning-Based Scoring Functions. Development and Applications with SAnDReS.

2020 ◽  
Vol 27 ◽  
Author(s):  
Gabriela Bitencourt-Ferreira ◽  
Camila Rizzotto ◽  
Walter Filgueira de Azevedo Junior
Keyword(s):  
Machine Learning ◽  
Binding Affinity ◽  
Drug Targets ◽  
Computational Models ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Predictive Performance ◽  
Machine Learning Techniques ◽  
Scoring Functions ◽  
Molegro Virtual Docker

Background: Analysis of atomic coordinates of protein-ligand complexes can provide three-dimensional data to generate computational models to evaluate binding affinity and thermodynamic state functions. Application of machine learning techniques can create models to assess protein-ligand potential energy and binding affinity. These methods show superior predictive performance when compared with classical scoring functions available in docking programs. Objective: Our purpose here is to review the development and application of the program SAnDReS. We describe the creation of machine learning models to assess the binding affinity of protein-ligand complexes. Method: SAnDReS implements machine learning methods available in the scikit-learn library. This program is available for download at https://github.com/azevedolab/sandres. SAnDReS uses crystallographic structures, binding, and thermodynamic data to create targeted scoring functions. Results: Recent applications of the program SAnDReS to drug targets such as Coagulation factor Xa, cyclin-dependent kinases, and HIV-1 protease were able to create targeted scoring functions to predict inhibition of these proteins. These targeted models outperform classical scoring functions. Conclusion: Here, we reviewed the development of machine learning scoring functions to predict binding affinity through the application of the program SAnDReS. Our studies show the superior predictive performance of the SAnDReS-developed models when compared with classical scoring functions available in the programs such as AutoDock4, Molegro Virtual Docker, and AutoDock Vina.

scholarly journals A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy

2021 ◽  
Author(s):  
Nicolas Fischer ◽  
Ean-Jeong Seo ◽  
Sara Abdelfatah ◽  
Edmond Fleischer ◽  
Anette Klinger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Virtual Screening ◽  
Small Molecules ◽  
Large Scale ◽  
Differentiation Therapy ◽  
P53 Expression ◽  
Microscale Thermophoresis ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Mcf 7

SummaryIntroduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a KD of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.

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