ABSTRACT
SARS-CoV-2 represents the causative agent of the current pandemic (COVID-19). The drug repurposing technique is used to search for possible drugs that can bind to SARS-CoV-2 proteins and inhibit viral replication. In this study, the FDA-approved antiplatelets are tested against the main protease and spike proteins of SARS-CoV-2 using in silico methods. Molecular docking and molecular dynamics simulation are used in the current study. The results suggest the effectiveness of vorapaxar, ticagrelor, cilostazol, cangrelor, and prasugrel in binding the main protease (Mpro) of SARS-CoV-2. At the same time, vorapaxar, ticagrelor, and cilostazol are the best binders of the spike protein. Therefore, these compounds could be successful candidates against COVID-19 that need to be tested experimentally.
Subject(s)
Antiviral Agents , Platelet Aggregation Inhibitors , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Cilostazol , Coronavirus 3C Proteases/antagonists & inhibitors , Humans , Lactones , Molecular Docking Simulation , Molecular Dynamics Simulation , Platelet Aggregation Inhibitors/pharmacology , Pyridines , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Ticagrelor , COVID-19 Drug TreatmentABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) that has emerged and rapidly spread across the world. The COVID-19 severity is associated to viral pneumonia with additional extrapulmonary complications. Hyperinflammation, dysfunctional immune response and hypercoagulability state are associated to poor prognosis. Therefore, the repositioning of multi-target drugs to control the hyperinflammation represents an important challenge for the scientific community. Cilostazol, a selective phosphodiesterase type-3 inhibitor (PDE-3), is an antiplatelet and vasodilator drug, that presents a range of pleiotropic effects, such as antiapoptotic, anti-inflammatory, antioxidant, and cardioprotective activities. Cilostazol also can inhibit the adenosine uptake, which enhances intracellular cAMP levels. In the lungs, elevated cAMP promotes anti-fibrotic, vasodilator, antiproliferative effects, as well as mitigating inflammatory events. Interestingly, a recent study evaluated antiplatelet FDA-approved drugs through molecular docking-based virtual screening on viral target proteins. This study revealed that cilostazol is a promising drug against COVID-19 by inhibiting both main protease (Mpro) and Spike glycoprotein, reinforcing its use as a promising therapeutic approach for COVID-19. Considering the complexity associated to COVID-19 pathophysiology and observing its main mechanisms, this article raises the hypothesis that cilostazol may act on important targets in development of the disease. This review highlights the importance of drug repurposing to address such an urgent clinical demand safely, effectively and at low cost, reinforcing the main pharmacological actions, to support the hypothesis that a multi-target drug such as cilostazol could play an important role in the treatment of COVID-19.
Subject(s)
COVID-19 Drug Treatment , Cilostazol/therapeutic use , Phosphodiesterase 3 Inhibitors/therapeutic use , SARS-CoV-2 , HumansABSTRACT
Coronavirus disease 2019 (COVID 19) was first identified in Wuhan, China near the end of 2019. To date, COVID-19 had spread to almost 235 countries and territories due to its highly infectious nature. Moreover, there is no vaccine or Food and Drug Administration (FDA)-approved drug. More time is needed to establish one of them. Consequently, the drug repurposing approach seems to be the most attractive and quick solution to accommodate this crisis. In this regard, we performed molecular docking-based virtual screening of antiplatelet FDA-approved drugs on the key two viral target proteins: main protease (Mpro ) and spike glycoprotein (S) as potential inhibitor candidates for COVID-19. In the present study, 15 antiplatelet FDA-approved drugs were investigated against the concerned targets using the Molecular Docking Server. Our study revealed that only cilostazol has the most favorable binding interaction on Mpro (PDB ID: 6LU7) and cilostazol, iloprost, epoprostenol, prasugrel, and icosapent ethyl have a higher binding affinity on spike glycoprotein (S) (PDB ID: 6VYB) compared with recent anti-CoVID-19. Therefore, cilostazol is a promising FDA drug against COVID-19 by inhibiting both Mpro and S protein. The insights gained in this study may be useful for quick approach against COVID-19 in the future.