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 Topical Sections

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.

References

[1]	Dhama K, Khan S, Tiwari R, et al. (2020) Coronavirus disease 2019–COVID-19. Clin Microbiol Rev 33: e00028-20. https://doi.org/10.1128/CMR.00028-20
[2]	World Health Organization, COVID-19 dashboard. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019
[3]	Malik YA (2020) Properties of coronavirus and SARS-CoV-2. Malays J Pathol 42: 3-11.
[4]	Prajapat M, Sarma P, Shekhar N, et al. (2020) Drug targets for corona virus: A systematic review. Indian J Pharmacol 52: 56-65. https://doi.org/10.4103/ijp.IJP_115_20
[5]	Hosseini R, Askari N (2023) A review of neurological side effects of COVID-19 vaccination. Eur J Med Res 28: 102. https://doi.org/10.1186/s40001-023-00992-0
[6]	Singh R, Bhardwaj VK, Purohit R (2022) Inhibition of nonstructural protein 15 of SARS-CoV-2 by golden spice: A computational insight. Cell Biochem Funct 40: 926-934. https://doi.org/10.1002/cbf.3753
[7]	Singh R, Bhardwaj VK, Sharma J, et al. (2021) Identification of potential plant bioactive as SARS-CoV-2 Spike protein and human ACE2 fusion inhibitors. Comput Biol Med 136: 104631. https://doi.org/10.1016/j.compbiomed.2021.104631
[8]	Singh R, Purohit R (2023) Multi-target approach against SARS-CoV-2 by stone apple molecules: A master key to drug design. Phytother Res 1–4. https://doi.org/10.1002/ptr.7772
[9]	Sharma J, Bhardwaj VK, Singh R, et al. (2021) An in-silico evaluation of different bioactive molecules of tea for their inhibition potency against non structural protein-15 of SARS-CoV-2. Food Chem 346: 128933. https://doi.org/10.1016/j.foodchem.2020.128933
[10]	Bhardwaj VK, Singh R, Sharma J, et al. (2021) Identification of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors. J Biomol Struct Dyn 39: 3449-3458. https://doi.org/10.1080/07391102.2020.1766572
[11]	Mishra GP, Bhadane RN, Panigrahi D, et al. (2021) The interaction of the bioflavonoids with five SARS-CoV-2 proteins targets: An in-silico study. Comput Biol Med 134: 104464. https://doi.org/10.1016/j.compbiomed.2021.104464
[12]	Panigrahi D, Mishra GP (2021) Virtual screening, molecular docking and in silico ADME-Tox analysis for identification of potential main protease (Mpro) enzyme inhibitors. Anti-Infe Agents 19: 79-95. https://doi.org/10.2174/2211352518999201208201854
[13]	Mishra A, Rathore AS (2022) RNA dependent RNA polymerase (RdRp) as a drug target for SARS-CoV2. J Biomol Struct Dyn 40: 6039-6051. https://doi.org/10.1080/07391102.2021.1875886
[14]	Elfiky AA (2020) Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci 253: 117592. https://doi.org/10.1016/j.lfs.2020.117592
[15]	Tarighi P, Eftekhari S, Chizari M, et al. (2021) A review of potential suggested drugs for coronavirus disease (COVID-19) treatment. Eur J Pharmacol 895: 173890. https://doi.org/10.1016/j.ejphar.2021.173890
[16]	Kim S, Chen J, Cheng T, et al. (2021) PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 49: D 1388-D1395.
[17]	Bai SB, Geethavani M, Ramakrishna C (2022) Synthesis characterization and molinspiration analysis, anti-bacterial activity of novel 2, 4, 6-tri substituted pyrimidines. J. Young Pharm 14: 174-178.
[18]	Wang Z, Pan H, Sun H, et al. (2022) fastDRH: A webserver to predict and analyze protein–ligand complexes based on molecular docking and MM/PB(GB)SA computation. Brief Bioinform 23: bbac201. https://doi.org/10.1093/bib/bbac201
[19]	Liu Y, Yang X, Gan J, et al. (2022) CB-Dock2: Improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Res 50: W159-W164. https://doi.org/10.1093/nar/gkac394
[20]	Madhulitha NR, Pradeep N, Sandeep S, et al. (2017) E-Pharmacophore Model Assisted Discovery of Novel Antagonists of nNOS. Biochem Anal Biochem 6: 307. https://doi.org/10.4172/2161-1009.1000307
[21]	Pasha A, Kumbhakar DV, Doneti R, et al. (2021) Inhibition of inducible nitric oxide synthase (iNOS) by andrographolide and in vitro evaluation of its antiproliferative and proapoptotic effects on cervical cancer. Oxid Med Cell Longev 2021: 6692628. https://doi.org/10.1155/2021/6692628
[22]	Katari SK, Natarajan P, Swargam S, et al. (2016) Inhibitor design against JNK1 through e-pharmacophore modeling docking and molecular dynamics simulations. J Recept Signal Transduct Res 36: 558-571. https://doi.org/10.3109/10799893.2016.1141955
[23]	Friesner RA, Banks JL, Murphy RB, et al. (2004) Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47: 1739-1749. https://doi.org/10.1021/jm0306430
[24]	Chiranjeevi P, Swargam S, Pradeep N, et al. (2016) Inhibitor design for VacA toxin of Helicobacter pylori. J Proteomics Bioinform 9: 220-225. https://doi.org/10.4172/jpb.1000409
[25]	Brańka AC (2000) Nosé-Hoover chain method for nonequilibrium molecular dynamics simulation. Phys Rev E 61: 4769-4773. https://doi.org/10.1103/PhysRevE.61.4769
[26]	Waterhouse A, Bertoni M, Bienert S, et al. (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 46: W296-W303. https://doi.org/10.1093/nar/gky427
[27]	Paysan-Lafosse T, Blum M, Chuguransky S, et al. (2023) InterPro in 2022. Nucleic Acids Res 51: D418-D427. https://doi.org/10.1093/nar/gkac993
[28]	Shah P, Westwell AD (2007) The role of fluorine in medicinal chemistry. J Enzyme Inhib Med Chem 22: 527-540. https://doi.org/10.1080/14756360701425014
[29]	Gupta SP (2019) Roles of fluorine in drug design and drug action. Lett Drug Des Discov 16: 1089-1109. https://doi.org/10.2174/1570180816666190130154726
[30]	Hydroxyl Group. Available from: https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/hydroxyl-group
[31]	Computational biology platform. Available from: https://www.computabio.com/applications-of-discovery-studio-software.html
[32]	Eastman RT, Roth JS, Brimacombe KR, et al. (2020) Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent Sci 6: 672-683. https://doi.org/10.1021/acscentsci.0c00489
[33]	Ramírez-Olivencia G, Estébanez M, Membrillo FJ, et al. (2019) Use of ribavirin in viruses other than hepatitis C. A review of the evidence. Enferm Infecc Microbiol Clin (Engl Ed) 37: 602-608. https://doi.org/10.1016/j.eimc.2018.05.008
[34]	Shiraki K, Daikoku T (2020) Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Therapeut 209: 107512. https://doi.org/10.1016/j.pharmthera.2020.107512
[35]	Lou Y, Liu L, Yao H, et al. (2021) Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: An exploratory randomized, controlled trial. Eur J Pharm Sci 157: 105631. https://doi.org/10.1016/j.ejps.2020.105631
[36]	Parang K, El-Sayed NS, Kazeminy AJ, et al. (2020) Comparative antiviral activity of remdesivir and anti-HIV nucleoside analogs against human coronavirus 229E (HCoV-229E). Molecules 25: 2343. https://doi.org/10.3390/molecules25102343
[37]	Aboul-Fotouh S, Mahmoud AN, Elnahas EM, et al. (2023) What are the current anti-COVID-19 drugs? From traditional to smart molecular mechanisms. Virol J 20: 241. https://doi.org/10.1186/s12985-023-02210-z
[38]	Tian L, Qiang T, Liang C, et al. (2021) RNA-dependent RNA polymerase (RdRp) inhibitors: the current landscape and repurposing for the COVID-19 pandemic. Eur J Med Chem 213: 113201. https://doi.org/10.1016/j.ejmech.2021.113201
[39]	Sanders JM, Monogue ML, Jodlowski TZ, et al. (2020) Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA 323: 1824-1836. https://doi.org/10.1001/jama.2020.6019
[40]	Oldenburg CE, Pinsky BA, Brogdon J, et al. (2021) Effect of oral azithromycin vs placebo on COVID-19 symptoms in outpatients with SARS-CoV-2 infection: A randomized clinical trial. JAMA 326: 490-498. https://doi.org/10.1001/jama.2021.11517
[41]	COVID-19 treatment guidelinesRemdesivir. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/remdesivir/

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