Promising drug Fondaparinux for the treatment of Covid-19: An in silico analysis of low molecular weight heparin, direct oral anticoagulant, and antiplatelet drug interactions with host protease furin

Purpose: As of July 2022, the Covid-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the D-dimer levels were increased in non-survivors compared to survivors and heparin treatment has begun to be administered to the patients in severe clinics. As we knew that the entrance of SARS-CoV2 to the host cell needs to be facilitated by host proteases; we published our hypothesis that heparin as a serine protease inhibitor may block the interaction between spike protein receptor-binding domain and host proteases. Methods: In this study, docking studies were carried out to evaluate the interactions between low molecular weight heparins (LMWHs) (enoxaparin, dalteparin, tinzaparin) direct oral anticoagulant and antiplatelet drugs with host proteases. Molecular docking studies were performed by using Schrödinger molecular modeling software. 3D structures of the ligands were obtained from the 2D structures by assigning the OPLS-2005 force field using the Maestro 12.7. The 3D crystal structure of the furin complexed with an inhibitor, 2,5-dideoksistreptamin derivative was extracted from the Protein Data Bank (PDB ID: 5MIM). Docking studies were carried out using the Grid-based Ligand Docking with Energetics module of the Schrödinger Software. Results: The docking studies revealed that fondaparinux was the most relevant molecule to interact with furin. It showed better interaction than the natural ligand of furin with an increased score compared to the docking score of -8.155 of the natural ligand. AnaGA*IsA structure representing LMWH structure has shown a docking score of -11.562 which was also better than the score of the natural ligand of furin. Conclusion: Our findings have shown that LMWHs, and fondaparinux can be used for their anticoagulant, anti-inflammatory and antiviral effects in Covid-19 patients. Clinical experience has shown that heparin and LMWH have effects of improving the prognosis of Covid-19 patients. A few studies have provided evidence of the safety and efficacy use of fondaparinux for venous thromboembolism prophylaxis in hospitalized Covid-19 patients. Our results have shown that in accordance with heparin and LMWH, fondaparinux can also be a candidate for ‘drug repurposing’ in Covid-19 therapy, not only because of their anticoagulant but also antiviral effects.