article · International Journal of Molecular Sciences
Computational and laboratory screening of thirty-four anticoagulant medicines identified several existing drugs capable of inhibiting the SARS-CoV-2 main protease. Initial molecular docking, molecular dynamics, and quantum mechanical simulations revealed strong binding affinities for idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor. Subsequent laboratory testing evaluated antiviral efficacy and cellular safety. Among the evaluated candidates, ticagrelor showed the strongest antiviral activity against SARS-CoV-2 with a half-maximal inhibitory concentration of 5.60 micromolar and a safety index of 25.33. Fondaparinux sodium and dabigatran also demonstrated clear antiviral inhibition alongside favourable safety profiles. In targeted enzyme assays against the main protease, fondaparinux sodium proved more than three times as potent as the reference standard tipranavir, while dabigatran also displayed substantial enzyme inhibition. These findings connect computational predictions with experimental evidence to outline structure-activity relationships for repurposed anticoagulants.
Repurposing approved drugs can substantially accelerate the identification of effective treatments for infectious diseases. Because severe COVID-19 frequently involves blood-clotting complications, discovering that specific clinical anticoagulants can also directly inhibit the viral main protease could provide dual therapeutic benefits. Demonstrating strong laboratory-based inhibition highlights specific molecules that warrant closer examination as potential therapeutic candidates.
This work could assist pharmaceutical developers and clinical researchers seeking repurposed drug candidates to treat COVID-19. Because the findings rely entirely on computational modelling and laboratory-based cell and enzyme assays, the research sits at an early stage. Substantial further testing, including animal studies and clinical trials, would be required before these anticoagulants could be repurposed commercially or clinically as targeted antiviral therapies.
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In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.
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DOI: 10.3390/ijms232012235
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