FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication

Abstract

Emergent novel SARS-CoV-2 is responsible for the current pandemic outbreak of severe acute respiratory syndrome with high mortality among the symptomatic population worldwide. Given the absence of a current vaccine or specific antiviral treatment, it is urgent to search for FDA-approved drugs that can potentially inhibit essential viral enzymes. The inhibition of 3CL pro has potential medical application, due to the fact that it is required for processing of the first translated replicase polyproteins into a series of native proteins, which are essential for viral replication in the host cell. We employed an in silico approach to test if disulfiram, as well as its metabolites, and captopril could be used as potential antiviral drugs against COVID-19. We provide data on the potential covalent interaction of disulfiram and its metabolites with the substrate binding subsite of 3CL pro and propose a possible mechanism for the irreversible protease inactivation thought the reaction of the aforementioned compounds with the Cys145. Although, captopril is shown to be a potential ligand of 3CL pro , it is not recommended anti-COVID-19 therapy, due to the fact that it can induce the expression of the viral cellular receptor such as, angiotensin-converting enzyme ACE-2, and thus, making the patient potentially more susceptible to infection. On the other hand, disulfiram, an alcoholism-averting drug, has been previously proposed as an antimicrobial and anti-SARS and MERS agent, safe to use even at higher doses with low side effects, it is recommended to be tested for control of SARS-CoV-2 infection.

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

“…Disulfiram, an FDA-approved gasdermin D inhibitor, blocks SARS-CoV-2 replication in silico ( Lobo-Galo et al, 2020 ). Moreover, disulfiram was shown to abrogate gasdermin D pore formation by covalent bonding to Cys191/Cys192 ( Hu et al, 2020 ).…”

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

“…The first studies faced the problem that the crystallographic structure of SARS-CoV-2 3CLpro was not available and hence relied on homology modeling; 175 , 176 the experimental resolution of the 3CLpro structure boosted a huge increase in molecular docking studies. 176 − 180 , 192 …”

“… 122 González-Paz et al 192 performed a blind-docking study to predict the binding of the B1a and B1b forms of the wide-range antiparasitic drug ivermectin ( Figure 10 ) to 3CLpro, suggesting that ivermectin B1a binds with a higher affinity than ivermectin B1b. Lobo-Galo et al 180 used a multiscale approach in which blind docking was first used to pinpoint the principal potential binding cavities, most often corresponding to the active site, and this region was subsequently selected for further focused docking. The authors screened thiol-reacting FDA-approved drugs including captopril (antihypertensive drug) and found that disulfiram, used to treat chronic alcoholism, has promising antiviral properties ( Figure 10 ).…”

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

“…Another co-crystal (PDB-ID 6Y2F/6Y2G), a-ketoamide inhibitor (13b) is also reported recently, providing the structural and residue-based architecture of catalytic sites . These co-crystals are paving the route for the application of virtual screening (VS) to get more efficacious molecules (Al-Khafaji et al, 2020;Kumar et al, 2020;Lobo-Galo et al, 2020).…”