Silibinin as potential tool against SARS‐Cov‐2: In silico spike receptor‐binding domain and main protease molecular docking analysis, and in vitro endothelial protective effects

Speciale, Antonio; Muscarà , Claudia; Molonia, Maria Sofia; Cimino, Francesco; Saija, Antonella; Giofrè, Salvatore Vincenzo

The spread of SARS‐CoV‐2, along with the lack of targeted medicaments, encouraged research of existing drugs for repurposing. The rapid response to SARS‐CoV‐2 infection comprises a complex interaction of cytokine storm, endothelial dysfunction, inflammation, and pathologic coagulation. Thus, active molecules targeting multiple steps in SARS‐CoV‐2 lifecycle are highly wanted. Herein we explored the in silico capability of silibinin from Silybum marianum to interact with the SARS‐CoV‐2 main target proteins, and the in vitro effects against cytokine‐induced‐inflammation and dysfunction in human umbilical vein endothelial cells (HUVECs). Computational analysis revealed that silibinin forms a stable complex with SARS‐CoV‐2 spike protein RBD, has good negative binding affinity with Mpro, and interacts with many residues on the active site of Mpro, thus supporting its potentiality in inhibiting viral entry and replication. Moreover, HUVECs pretreatment with silibinin reduced TNF‐α‐induced gene expression of the proinflammatory genes IL‐6 and MCP‐1, as well as of PAI‐1, a critical factor in coagulopathy and thrombosis, and of ET‐1, a peptide involved in hemostatic vasoconstriction. Then, due to endothelium antiinflammatory and anticoagulant properties of silibinin and its capability to interact with SARS‐CoV‐2 main target proteins demonstrated herein, silibinin could be a strong candidate for COVID‐19 management from a multitarget perspective.