Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches

Abstract

Most recently, the new coronavirus (SARS-CoV-2) has been recognized as a pandemic by the World Health Organization (WHO) while this virus shares substantial similarity with SARS-CoV. So far, no definitive vaccine or drug has been developed to cure Covid-19 disease, since many important aspects about Covid-19 such as pathogenesis and proliferation pathways are still unclear. It was proven that human ACE2 is the main receptor for the entry of Covid-19 into lower respiratory tract epithelial cells through interaction with SARS-CoV-2 S protein. Based on this observation, it is expected that the virus infection can be inhibited if protein-protein interaction is prevented. In this study, using structurebased virtual screening of FDA databases, several lead drugs were discovered based on the ACE2binding pocket of SARS-CoV-2 S protein. Then, binding affinity, binding modes, critical interactions, and pharmaceutical properties of the lead drugs were evaluated. Among the previously approved drugs, Diammonium Glycyrrhizinate, Digitoxin, Ivermectin, Rapamycin, Rifaximin, and Amphotericin B represented the most desirable features, and can be possible candidates for Covid-19 therapies. Furthermore, molecular dynamics (MD) simulation was accomplished for three S protein/drug complexes with the highest binding affinity and best conformation and binding free energies were also computed with the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Results demonstrated the stable binding of these compounds to the S protein; however, in order to confirm the curative effect of these drugs, clinical trials must be done.

Pinpointing the potential hits for hindering interaction of SARS-CoV-2 S-protein with ACE2 from the pool of antiviral phytochemicals utilizing molecular docking and molecular dynamics (MD) simulations

“…Efforts are also made for repurposing approved drugs as inhibitors of S-protein of SARS-CoV-2 where the authors have proposed 10 FDA approved drugs showing potentials to interact and mask the RBD [ 42 ]. Of lately, strategy of repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches is used where drugs, Diammonium Glycyrrhizinate, Digitoxin, Ivermectin, Rapamycin, Rifaximin, and Amphotericin B represented the most desirable features to serve as RBD blockers [ 43 ]. Similar other study showed laxative drug, Bisoxatin to have potentials act as RBD blocker [ 44 ].…”

How glycobiology can help us treat and beat the COVID-19 pandemic

“…Repurposing of FDA-approved small molecule drug inhibitors of SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches showed Digitoxin cardiac glycoside as a good therapeutic candidate drug ( 94 , 95 ). Antiviral activity of Digoxin and Ouabain cardiac aminoglycosides against SARS-CoV-2 infection was recently demonstrated ( 96 ), thus suggesting these cardiac aminoglycosides may be alternative treatments for COVID-19 with additional benefits for cardiovascular disease patients ( Table 1 and Figure 5 ).…”

Targeting protein-protein interaction interfaces in COVID-19 drug discovery

“…Kalhor et al conducted structure-based virtual screening with FDA approved drug databases to discover the PPI inhibitors against S-ACE2 complex. They identified 6 compounds can bind to the ACE2 binding pocket on SARS-CoV-2 S protein, from which they further proposed Diammonium Glycyrrhizinate as the most potent compound by MD simulation technique [78] . Hanson et al also developed an AlphaLISA RBD − ACE2 platform to facilitate the screening of PPII inhibitors perturbing this host–pathogen interaction.…”