Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach

Int J Biol Macromol. 2020 Nov 15;163:1787-1797. doi: 10.1016/j.ijbiomac.2020.09.098. Epub 2020 Sep 17.

Abstract

The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.

Keywords: COVID-19; Drug; RNA-dependent RNA polymerase; SARS-CoV-2.

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / enzymology
  • COVID-19
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / virology
  • Drug Repositioning*
  • Fidaxomicin / chemistry
  • Fidaxomicin / pharmacology
  • Humans
  • Ivermectin / chemistry
  • Ivermectin / pharmacology
  • Molecular Docking Simulation
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / virology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • Rifabutin / chemistry
  • Rifabutin / pharmacology
  • Rifampin / analogs & derivatives
  • Rifampin / chemistry
  • Rifampin / pharmacology
  • SARS-CoV-2
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Rifabutin
  • Ivermectin
  • RNA-Dependent RNA Polymerase
  • Rifampin
  • rifapentine
  • Fidaxomicin

Supplementary concepts

  • COVID-19 drug treatment