Repurposed drug molecules targeting NSP12 protein of SARS-CoV-2: An in-silico study

Bhawna Sharma; Bennet Angel; Vankadoth Umakanth Naik; Annette Angel; Vinod Joshi; BM Shareef; Neha Singh; Ambreen Shafaat Khan; Poorna Khaneja; Shilpa Barthwal; Ramesh Joshi; Nuzhat Maqbool Peer; Kiran Yadav; Komal Tomar; Satendra Pal Singh; Bhawna Sharma; Bennet Angel; Vankadoth Umakanth Naik; Annette Angel; Vinod Joshi; BM Shareef; Neha Singh; Ambreen Shafaat Khan; Poorna Khaneja; Shilpa Barthwal; Ramesh Joshi; Nuzhat Maqbool Peer; Kiran Yadav; Komal Tomar; Satendra Pal Singh

doi:10.3934/molsci.2023019

AIMS Molecular Science

2023, Volume 10, Issue 4: 322-342. doi: 10.3934/molsci.2023019

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Research article

Repurposed drug molecules targeting NSP12 protein of SARS-CoV-2: An in-silico study

1.
Centre of Excellence in Virology & Immunology, Sharda University, Greater Noida, 201310-Uttar Pradesh, India
2.
Dept. of Bioinformatics, Sri Venkateswara Institute of Medical Sciences, Tirupati, 517502-Andra Pradesh, India
3.
Sharda School of Agricultural Sciences, Sharda University, Greater Noida, 201310-Uttar Pradesh, India
4.
Dept of Microbiology, Sharda School of Medical Sciences & Research, Greater Noida, 201310-Uttar Pradesh, India

Received: 17 September 2023 Revised: 05 December 2023 Accepted: 11 December 2023 Published: 25 December 2023

The emergence of SARS-CoV-2 created a havoc worldwide, causing high morbidity, serious complications and mortality. The ORF1ab of SARS-CoV-2 has 16 non-structural proteins which are required for genome replication and transcription. All of these are druggable targets, of which NSP12 (RNA-dependent RNA polymerase), was selected as a potential target for drug molecules. Remdesivir is a recommended drug for SARS-CoV-2 and it targets the RdRp protein. Although Remdesivir was given to COVID-19 patients based on their clinical manifestations, yet the transmission and spread of the virus continued and to add to its pandemicity, new variants emerged from time to time. This necessitates the need for molecular modification of existing antiviral drugs so that more precise targets for halting viral replication can be selected. For this, the approach used was repurposing of the existing drugs. In the present study, ten FDA-approved drugs were chosen on the basis of their properties of inhibiting the RdRp protein. These drugs were subjected for checking the docking score with the target protein. Of these, Remdesivir, Ribavirin, Favipiravir and Baloxavir were taken for further analysis on the basis of their best scores. These drugs were then modified to check the efficiency to inhibit the RdRp and to stop the replication rate of the virus. We docked the modified drugs with the macrodomain of RdRp by using the CB-Dock web server and checked the binding affinity and amino acid contact residues. The modified drugs were also checked for bioactivity in the Molinspiration cheminformatics online tool. Our results showed increased affinity for RdRp of SARS-CoV-2 when compared to the original compound. We also checked the synthetic accessibility of the drugs using the SwissADME tool. The study showed promising results when modified. The findings reported need further confirmation through wet lab studies.
- SARS-CoV-2,
- remdesivir,
- RdRp,
- respiratory drugs,
- docking,
- MD simulation
Citation: Bhawna Sharma, Bennet Angel, Vankadoth Umakanth Naik, Annette Angel, Vinod Joshi, BM Shareef, Neha Singh, Ambreen Shafaat Khan, Poorna Khaneja, Shilpa Barthwal, Ramesh Joshi, Nuzhat Maqbool Peer, Kiran Yadav, Komal Tomar, Satendra Pal Singh. Repurposed drug molecules targeting NSP12 protein of SARS-CoV-2: An in-silico study[J]. AIMS Molecular Science, 2023, 10(4): 322-342. doi: 10.3934/molsci.2023019

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Abstract

The emergence of SARS-CoV-2 created a havoc worldwide, causing high morbidity, serious complications and mortality. The ORF1ab of SARS-CoV-2 has 16 non-structural proteins which are required for genome replication and transcription. All of these are druggable targets, of which NSP12 (RNA-dependent RNA polymerase), was selected as a potential target for drug molecules. Remdesivir is a recommended drug for SARS-CoV-2 and it targets the RdRp protein. Although Remdesivir was given to COVID-19 patients based on their clinical manifestations, yet the transmission and spread of the virus continued and to add to its pandemicity, new variants emerged from time to time. This necessitates the need for molecular modification of existing antiviral drugs so that more precise targets for halting viral replication can be selected. For this, the approach used was repurposing of the existing drugs. In the present study, ten FDA-approved drugs were chosen on the basis of their properties of inhibiting the RdRp protein. These drugs were subjected for checking the docking score with the target protein. Of these, Remdesivir, Ribavirin, Favipiravir and Baloxavir were taken for further analysis on the basis of their best scores. These drugs were then modified to check the efficiency to inhibit the RdRp and to stop the replication rate of the virus. We docked the modified drugs with the macrodomain of RdRp by using the CB-Dock web server and checked the binding affinity and amino acid contact residues. The modified drugs were also checked for bioactivity in the Molinspiration cheminformatics online tool. Our results showed increased affinity for RdRp of SARS-CoV-2 when compared to the original compound. We also checked the synthetic accessibility of the drugs using the SwissADME tool. The study showed promising results when modified. The findings reported need further confirmation through wet lab studies.

Acknowledgments

We would like to thank the Indian Council of Medical Research, New Delhi, India, for funding this study (Grant number 2021-6369).

Conflict of interest

The authors declare no conflict of interest.

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