Identification of natural compounds as SARS-CoV-2 entry inhibitors by molecular docking-based virtual screening with bio-layer interferometry

Abstract

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 μM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

“…Bio-layer interferometry allows the calculation of the association rate (k on ), dissociation rate (k dis ) and dissociation constant (K D ). This technique has been adopted to screen RBD ligands [17,48] in combination with virtual screening [49,50]. The results of the bio-layer experiments are presented in Table 1.…”

Structure-based docking, pharmacokinetic evaluation, and molecular dynamics-guided evaluation of traditional formulation against SARS-CoV-2 spike protein receptor bind domain and ACE2 receptor complex

“…On a literature survey, it was found that vasicine has shown activity against Influenza Virus Infection (Chavan et al 2013 ). Iso-chlorogenic acid has a potent anti-hepatitis B activity (Hao et al 2012 ), and antienterovirus (Cao et al 2017 ), one of its derivate iso-chlorogenic acid A has been proven by the in vitro study to inhibit viral entry into the cell at 100 micromolar concentration (Zhang et al 2021 ). Catechin inhibits both Mpro and spike protein of SARS-CoV-2 predicted by using computational study (Srivastava et al 2020 ).…”

Possibility as role of ginseng and ginsenosides on inhibiting the heart disease of COVID-19: A systematic review

“…When infected with COVID-19, SARS-CoV-2 first binds to ACE2 present in the cell membrane, enters the cell, and abnormally changes the ACE2 signaling transduction, resulting in acute myocarditis and lung damage [ 18 ]. That is, normally ACE2 were expressed in the cell membranes of the heart and lungs, and receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein binds to each other with ACE2 and enters the heart and lung tissue cells through interaction, thereby inhibiting the function of the ACE2 can block SARS-CoV-2 virus infection [ 19 ] ( Fig. 3 ).…”

“…In line with the above observations, 20(S)-ginsenoside Rg3, the main active ingredient of panax ginseng, blocks RBD-ACE2 interaction through direct inhibition of RBD of the SARS-CoV-2 spike glycoprotein. That is, RBDof SARS-CoV-2 spike glycoproteins to cell membranes in the heart and lung tissue were blocked by 20(S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3 [ 19 ]. In addition, recent studies have shown that 20(S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3 effectively inhibited viral infection of SARS-CoV-2-like lentivirus and SARS-CoV-2 virus in cells expressing receptors of human SARS-CoV-2 spike glycoprotein.…”

“…These results indicate that 20(S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3, which are the main active ingredients of panax ginseng, directly inhibit the RBD of SARS-CoV-2 spike glycoproteins, ultimately preventing a viral infection. That is, treatment of 20(S)-ginsenosides Rg3 and 20(R)-ginsenoside Rg3 indicates the possibility that the risk of antiviral infection can be reduced by inhibiting the interconnection between the RBD of SARS-CoV-2 spike glycoproteins and ACE2 expressed in cardiomyocytes [ 19 ]. On the other hand, unlike immune antibodies, 20(S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3 effectively inhibit binding with ACE2 by targeting regions of receptors per SARS-CoV-2 spike, which are not accessible to biomolecules.…”