In Silico Drug Repurposing for SARS-CoV-2 Main Proteinase and Spike Proteins

Abstract

The pandemic caused by SARS-CoV-2 is currently representing a major health and economic threat to humanity. So far, no specific treatment to this viral infection has been developed and the emergency still requires an efficient intervention. In this work, we used virtual screening to facilitate drug repurposing against SARS-CoV-2, targeting viral main proteinase and spike protein with 3000 existing drugs. We used a protocol based on a docking step followed by a short molecular dynamic simulation and rescoring by the Nwat-MMGBSA approach. Our results provide suggestions for prioritizing in vitro and/or in vivo tests of already available compounds.

Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor

“…The same study also reported potential binding of indinavir to RdRp [ 56 ]. Several other studies also reported indinavir as a potential drug to target M pro /3CL pro [ 46 , 47 , 55 , 57 , 58 ]. Indu et al also reported good bioavailability of indinavir [ 56 ].…”

“…Except indinavir, the others (Pibrentasvir, baloxavir marboxil, doravirine, maraviroc, and nelfinavir) have been shown to cause rare cases of hepatotoxicity in toxicological studies [ 44 ]. Maffucci and Contini predicted binding of indinavir to ACE2 at the site that overlaps with the binding of SARS-CoV-2 spike protein [ 55 ]. In a virtual screening of 65 FDA approved small molecule antiviral drugs against the main protease (Mpro, also called 3CL pro ) and the RNA-dependent RNA polymerase (RdRp), indinavir and pibrentasvir were predicted to bind Mpro of SARS-CoV-2 [ 56 ].…”

“…Although treatment with posaconazole causes transient elevations in serum aminotransferase levels in 2%–12% of patients, these elevations are usually mild, asymptomatic and self-limited and rarely require discontinuation of the medication [ 44 ]. Recent studies also reported binding of nystatin and posaconazol against SARS-CoV-2 spike protein binding site [ 55 ] and M pro [ 58 ]. Mohammed et al reported potential binding of Amphotericin B to M pro [ 58 ].…”

“…Azilsartan kamedoxomil is a potassium salt of azilsartan medoxomil. A recent study predicted binding of azilsartan and zafirlukast to the SARS-CoV-2 binding site [ 55 ]. Icatibant, a drug used to treat hereditary angioedema, was recently reported to bind against SARS-CoV-2 binding site [ 55 ] as well as the M pro [ 58 ].…”

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“…Several computational drug screening methods based on molecular docking, deep learning or Molecular Dynamics (MD) simulations have been applied in drug repositioning studies for COVID-19 [9,[11][12][13][14]. However, most of these normally rely on a single technique or lacks experimental validation.…”