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

Abstract

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.

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs

“…Quercetin’s bioavailability is comparatively better but remains constrained by intestinal efflux and biliary excretion [ 64 ]. More promisingly, EGCG, hispidulin, icariin, quercetin, and rutin can cross the BBB; silibinin cannot, while the permeability of chrysin and formononetin remains unclear [ 17 , 65 , 66 , 67 , 68 ]. In this light, developing novel formulations to enhance the bioavailability and brain delivery of flavonoids is of key interest in advancing synergistic anti-GBM therapy.…”

QSAR, molecular docking and ADMET properties in silico studies of novel 4,5,6,7-tetrahydrobenzo[D]-thiazol-2-Yl derivatives derived from dimedone as potent anti-tumor agents through inhibition of C-Met receptor tyrosine kinase

“… In terms of distribution indicators, the size of the distribution (VDss) is considered high if its value is greater than 0.45 [ 75 ]. The standard value for blood-brain barrier (BBB) permeability is good if its value is more than 0.3 and poor if LogBB < -1 [ 76 ]. For the CNS index, compounds with LogPS > -2 are considered capable of penetrating the CNS, whereas compounds with LogPS < -3 are considered incapable of penetrating the CNS [ 77 ].…”

Phytocompounds and COVID‐19: Two years of knowledge

“…The present virtual issue contains review addressing the potential of flavonoids, curcumin, resveratrol and silibinin in attenuating lung injury and cytokine storm associated with the disease (Derosa et al, 2021 ; Di Petrillo, Orrù, Fais, & Fantini, 2021 ; El‐Missiry, Fekri, Kesar, & Othman, 2021 ; Gour, Manhas, Bag, Gorain, & Nandi, 2021 ; Khezri, Saeedi, Mohammadamini, & Zakaryaei, 2021 ; Palit, Mukhopadhyay, & Chattopadhyay, 2021 ; Pawar & Pal, 2020 ; Santana et al, 2021 ). Studies on specific polyphenols showed that (a) kaempferol inhibited the SARS‐CoV‐2 main protease (3CLpro) (Khan et al, 2021 ), (b) oroxylin suppressed the entrance of the SARS‐CoV‐2‐spiked pseudotyped virus into ACE2 cells (Gao et al, 2021 ), (c) resveratrol inhibited the replication of SARS‐CoV‐2 in cultured Vero cells (M. Yang et al, 2021 ) and (d) silibinin interacted with SARS‐CoV‐2 main target proteins (e.g., spike protein RBD and Mpro residues) (Speciale et al, 2021 ). Clinical investigations showed the efficacy of nano‐curcumin formulations in the management of mild to moderate hospitalized patients, being curcumin able to accelerate the recovery of the acute inflammatory phase (Hassaniazad et al, 2021 ; Saber‐Moghaddam et al, 2021 ).…”