A computational drug repurposing approach in identifying the cephalosporin antibiotic and anti-hepatitis C drug derivatives for COVID-19 treatment

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 1.4 million deaths worldwide. Repurposing existing drugs offers the fastest opportunity to identify new indications for existing drugs as a stable solution against coronavirus disease 2019 (COVID-19). The SARS-CoV-2 main protease (M pro ) is a critical target for designing potent antiviral agents against COVID-19. In this study, we identify potential inhibitors against COVID-19, using an amalgam of virtual screening, molecular dynamics (MD) simulations, and binding-free energy approaches from the Korea Chemical Bank drug repurposing (KCB-DR) database. The database screening of KCB-DR resulted in 149 binders. The dynamics of protein-drug complex formation for the seven top scoring drugs were investigated through MD simulations. Six drugs showed stable binding with active site of SARS-CoV-2 M pro indicated by steady RMSD of protein backbone atoms and potential energy profiles. Furthermore, binding free energy calculations suggested the community-acquired bacterial pneumonia drug ceftaroline fosamil and the hepatitis C virus (HCV) protease inhibitor telaprevir are potent inhibitors against M pro . Molecular dynamics and interaction analysis revealed that ceftaroline fosamil and telaprevir form hydrogen bonds with important active site residues such as Thr24, Thr25, His41, Thr45, Gly143, Ser144, Cys145, and Glu166 that is supported by crystallographic information of known inhibitors. Telaprevir has potential side effects, but its derivatives have good pharmacokinetic properties and are suggested to bind M pro . We suggest the telaprevir derivatives and ceftaroline fosamil bind tightly with SARS-CoV-2 M pro and should be validated through preclinical testing.

Insilico drug repurposing using FDA approved drugs against Membrane protein of SARS-CoV-2

“…Topology parameters of the potential drug candidates were generated by using SwissParam server 42 . Thereafter, these complexes were simulated for 50 ns using GROningen MAchine for Chemical Simulations (GROMACS v5.1.5) 43 , following the same protocol as described in our previous report 44 .…”

“…44,61,66 . The protein-drug molecular interactions were also stabilized by non-polar interactions within the active site residues of the protein.…”

Effects of Immune System-Related Medications on COVID-19 Outcome in a Cohort of Iranian Patients: Preliminary Report of a Data Mining Study

“…In general, the associations of antibiotics with COVID-19 outcome are discussed with two aims: one of them is their effect on bacterial coinfections, and the second one is their antiviral effect. A computational analysis showed that chephalosporins had a potential binding ability to SARS-Cov-2 [ 15 ]. If an antibiotic shows a harmful effect, it may be representative of the effect of an underlying bacterial infection.…”

Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

“…Molecular dynamics (MD) simulations are applied to understand the protein-ligand interactions at the atomic level in order to scrutinize their conformational flexibility and structural stability under physiological conditions [ 75 , 76 ]. The complexes obtained from the process of molecular docking were subjected to MD simulations in GROningen MAchine for Chemical Simulations ( GROMACS v2018) [ 77 ] with the docked structures of compounds with Hpse as initial coordinates.…”