In silico study indicates antimalarials as direct inhibitors of SARS-CoV-2-RNA dependent RNA polymerase

Abstract

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic. RNA-dependent RNA polymerase (RdRp) is the key component of the replication or transcription machinery of coronavirus. Therefore SARS-CoV-2-RdRp has been chosen as an important target for the development of antiviral drug(s). During the early pandemic of the COVID-19, chloroquine and hydroxychloroquine were suggested by the researchers for the prevention or treatment of SARS-CoV-2. In our study, the antimalarial compounds have been screened and docked against SARS-CoV-2-RdRp (PDB ID: 7BTF), and it was observed that the antimalarials chloroquine, hydroxychloroquine, and amodiaquine exhibit good affinity. Since the crystal structure of SARS-CoV-2-RdRp with its substrate is not available, poliovirus-RdRp crystal structure co-crystallized with its substrate ATP (PDB ID: 2ILY) was used as a reference structure. The superimposition of SARS-CoV-2-RdRp and poliovirus-RdRp structures showed that the active sites of both of the RdRps superimposed very well. The amino acid residues involved in the binding of ATP in the case of poliovirus-RdRp and residues involved in binding with the antimalarial compounds with SARS-CoV-2-RdRp were compared. In both cases, the conserved residues were found to be involved in establishing the interactions. The MMGBSA and molecular dynamic simulation studies were performed to strengthen our docking results. Further residues involved in binding of antimalarials with SARS-CoV-2-RdRp were compared with the residues involved in the SARS-CoV-2-RdRp complexed with remdesivir [PDB ID: 7BV2]. It was observed that co-crystallized remdesivir and docked antimalarials bind in the same pocket of SARS-CoV-2 -RdRp.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• SARS-CoV-2-RNA dependent RNA polymerase
• antimalarials
• MD simulation
• in silico inhibition

Acknowledgements

We are also thankful to Ms. Priyanka Tiwari, Department of Biochemistry, University of Allahabad, Allahabad, for her technical support. The authors are grateful to UGC-SAP and DST-FIST for their generous support towards creating research facilities at the Department of Biochemistry of the University of Allahabad, Allahabad, India.

Disclosure statement

The authors declare that they do not have any conflicts of interest.

Additional information

Funding

PKD is thankful to UGC-New Delhi for supporting him in the form of a Dr. D.S. Kothari Post-Doctoral Research Fellowship. BS acknowledges UPCST-Lucknow for the support in the form of a Research Grant.