Identification of a repurposed drug as an inhibitor of Spike protein of human coronavirus SARS-CoV-2 by computational methods

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein-ACE2 interface by making substantial p-p interactions with Tyr505 in the 'Site 1' hook region of RBD and hydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.

Dieckol and Its Derivatives as Potential Inhibitors of SARS-CoV-2 Spike Protein (UK Strain: VUI 202012/01): A Computational Study

“…Furthermore, previous reports suggest a disagreement between docking Δ G and MM-GBSA Δ G bind determined using Prime module [ 29 , 30 , 31 ]. Many ligands have been shown to bind the RBD of Spike protein with an estimated value of Δ G bind in the range of −21.45 to −54.11 kcal/mol, which is close to our estimated value [ 32 , 33 ]. Interestingly, the Prime/MM-GBSA values of lomitapide, dihydroergotamine mesylate, and olaparib against the Spike protein of SARS-CoV-2 have been estimated to be −98.46, −84.67, and −80.19, respectively [ 34 ].…”

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

“…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 ]. S-protein is additionally focused with the most ordinarily discovered phytochemicals, where Kaempferol, Quercetin, and Fisetin had been appeared to bind and block the RBD which is validated utilizing molecular docking and MD reenactments [ 45 ].…”

Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections

“…Assumption of folic acid has been observed to protect pregnant women from SARS-CoV-2 infection, with contrasting evidence suggesting that it may either inhibit the furin protease, needed by the virus to enter the host cell, or the protease 3CL pro , essential for viral replication [ 37 ]. As a small-molecule antiviral agent, tegobuvir has been evaluated in clinical trials for COVID-19 [ 38 ], while bisoxatin (DB09219) has been suggested as a potential inhibitor of SARS-CoV-2 spike protein following a computational approach [ 39 ]. Amodiaquine has been found to inhibit SARS-CoV-2 replication in vitro [ 40 ], ketanserin has been suggested as a potential additive drug to improve the ventilation/perfusion mismatch in patients with COVID-19 [ 41 ] and, finally, the anti-HIV drug raltegravir has been proposed as a potential 3CL pro inhibitor following a computational approach [ 42 ].…”