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Repurposing of FDA-approved antivirals, antibiotics, anthelmintics, antioxidants, and cell protectives against SARS-CoV-2 papain-like protease.

ABSTRACT: SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papain-like protease (PLpro) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PLpro strongly were three cell protectives and antioxidants (NAD+, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine, and zanamivir), two antimicrobials (doripenem and sulfaguanidine), two anticancer drugs, three benzimidazole anthelmintics, one antacid (famotidine), three anti-hypertensive ACE receptor blockers (candesartan, losartan, and valsartan) and other miscellaneous systemically or topically acting drugs. The binding patterns of these drugs were superior to the previously identified SARS CoV PLpro inhibitor, 6-mercaptopurine (6-MP), suggesting a potential for repurposing these drugs to treat COVID-19. The objective of drug repurposing is the rapid relocation of safe and approved drugs by bypassing the lengthy pharmacokinetic, toxicity, and preclinical phases. The ten drugs with the highest estimated docking scores with favorable pharmacokinetics were subjected to molecular dynamics (MD) simulations followed by molecular mechanics/generalized Born surface area (MM/GBSA) binding energy calculations. Phenformin, quercetin, and ritonavir all demonstrated prospective binding affinities for COVID-19 PLpro over 50?ns MD simulations, with binding energy values of -56.6, -40.9, and -37.6?kcal/mol, respectively. Energetic and structural analyses showed phenformin was more stable than quercetin and ritonavir. The list of the drugs provided herein constitutes a primer for clinical application in COVID-19 patients and guidance for further antiviral studies.Communicated by Ramaswamy H. Sarma.

SUBMITTER: Kandeel M

PROVIDER: S-EPMC7332862 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Repurposing of FDA-approved antivirals, antibiotics, anthelmintics, antioxidants, and cell protectives against SARS-CoV-2 papain-like protease.

Kandeel Mahmoud M Abdelrahman Alaa H M AHM Oh-Hashi Kentaro K Ibrahim Abdelazim A Venugopala Katharigatta N KN Morsy Mohamed A MA Ibrahim Mahmoud A A MAA

Journal of biomolecular structure & dynamics 20200629 14

SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PL<sup>pro</sup> strongly were three cell protectives and antioxidants (NAD+, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine ...[more]

PMID: 32597315

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Project description:The RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) from SARS-CoV-2 play crucial roles in the viral life cycle and are considered the most promising targets for drug discovery against SARS-CoV-2. In this study, FDA-approved drugs were screened to identify the probable anti-RdRp and 3CLpro inhibitors by molecular docking approach. The number of ligands selected from the PubChem database of NCBI for screening was 1760. Ligands were energy minimized using Open Babel. The RdRp and 3CLpro protein sequences were retrieved from the NCBI database. For Homology Modeling predictions, we used the Swiss model server. Their structure was then energetically minimized using SPDB viewer software and visualized in the CHIMERA UCSF software. Molecular dockings were performed using AutoDock Vina, and candidate drugs were selected based on binding affinity (∆G). Hydrogen bonding and hydrophobic interactions between ligands and proteins were visualized using Ligplot and the Discovery Studio Visualizer v3.0 software. Our results showed 58 drugs against RdRp, which had binding energy of - 8.5 or less, and 69 drugs to inhibit the 3CLpro enzyme with a binding energy of - 8.1 or less. Six drugs based on binding energy and number of hydrogen bonds were chosen for the next step of molecular dynamics (MD) simulations to investigate drug-protein interactions (including Nilotinib, Imatinib and dihydroergotamine for 3clpro and Lapatinib, Dexasone and Relategravir for RdRp). Except for Lapatinib, other drugs-complexes were stable during MD simulation. Raltegravir, an anti-HIV drug, was observed to be the best compound against RdRp based on docking binding energy (-9.5 kcal/mole) and MD results. According to the MD results and binding energy, dihydroergotamine is a suitable candidate for 3clpro inhibition (-9.6 kcal/mol). These drugs were classified into several categories, including antiviral, antibacterial, anti-inflammatory, anti-allergic, cardiovascular, anticoagulant, BPH and impotence, antipsychotic, antimigraine, anticancer, and so on. The common prescription-indications for some of these medication categories appeared somewhat in line with manifestations of COVID-19. We hope that they can be beneficial for patients with certain specific symptoms of SARS-CoV-2 infection, but they can also probably inhibit viral enzymes. We recommend further experimental evaluations in vitro and in vivo on these FDA-approved drugs to assess their potential antiviral effect on SARS-CoV-2.

Dataset Information

Repurposing of FDA-approved antivirals, antibiotics, anthelmintics, antioxidants, and cell protectives against SARS-CoV-2 papain-like protease.

Publications

Repurposing of FDA-approved antivirals, antibiotics, anthelmintics, antioxidants, and cell protectives against SARS-CoV-2 papain-like protease.

Similar Datasets

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