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Investigation of The Potential Inhibitor Effects Of Lycorine On Sars-Cov-2 Main Protease (Mpro) Using Molecular Dynamics Simulations and MMPBSA

Year 2022, Volume: 5 Issue: 3, 424 - 435, 15.12.2022

Barış Kurt

https://doi.org/10.38001/ijlsb.1110761
Cited By: 3

Abstract

The main protease (Mpro or 3CLpro) plays important roles in viral replication and is one of attractive targets for drug development for SARS-CoV-2. In this study, we investigated the potential inhibitory effect of lycorine molecule as a ligand on SARS-CoV-2 using computational approaches. For this purpose, we conducted molecular docking and molecular dynamics simulations MM-PB(GB)SA analyses. The findings showed that the lycorine ligand was successfully docked with catalytic dyad (Cys145 and His41) of SARS-CoV-2 Mpro with binding affinity changing between -6.71 and -7.03 kcal mol-1. MMPB(GB)SA calculations resulted according to GB (Generalized Born) approach in a Gibbs free energy changing between -24.925-+01152 kcal/mol between lycorine and SARS-CoV-2 which is promising. PB (Poisson Boltzmann) approach gave less favorable energy (-2.610±0.2611 kcal mol-1). Thus, Entropy calculations from the normal mode analysis (ΔS) were performed and it supported GB approach and conducted -23.100±6.4635 kcal mol-1. These results showed lycorine has a druggable potential but the drug effect of lycorine on COVID-19 is limited and experimental studies should be done with pharmacokinetic modifications that increase the drug effect of lycorine.

Keywords

Molecular Dynamics Simulation MMPBSA Gibbs Energy SARS-CoV-2

References

  • 1. Weiss SR, Navas-Martin S. Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus. Microbiol Mol Biol Rev. 2005. 69(4):635–64.
  • 2. Ji W, Wang W, Zhao X, Zai J, Li X. Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol. 2020.
  • 3. Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomed. 2020. 91(1):157–60.
  • 4. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020. 579(7798):265–9.
  • 5. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019. 17(3):181–92.
  • 6. Zhou P, Yang X Lou, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020. 579(7798):270–3.
  • 7. Ghosh AK, Xi K, Ratia K, Santarsiero BD, Fu W, Harcourt BH, et al. Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors. J Med Chem. 2005 Nov. 48(22):6767–71.
  • 8. Dömling A, Gao L. Chemistry and Biology of SARS-CoV-2. Chem. 2020. 6(6):1283–95.
  • 9. Needle D, Lountos GT, Waugh DS. Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity. Acta Crystallogr Sect D Biol Crystallogr. 2015. 71:1102–11.
  • 10. Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. ( 3CL pro ) Structure : Basis for Design of Anti-SARS Drugs. Science (80- ). 2003. 300(June):1763–7.
  • 11. Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen LL. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020. (xxxx):1–7.
  • 12. Callaway E. Beyond Omicron: what’s next for COVID’s viral evolution. Nature. 2021. 600(7888):204–7.
  • 13. Shen JW, Ruan Y, Ren W, Ma BJ, Wang XL, Zheng CF. Lycorine: A potential broad-spectrum agent against crop pathogenic fungi. J Microbiol Biotechnol. 2014. 24(3):354–8.
  • 14. Shawky E. In-silico profiling of the biological activities of Amaryllidaceae alkaloids. J Pharm Pharmacol. 2017. 69(11):1592–605.
  • 15. Szlávik L, Gyuris Á, Minárovits J, Forgo P, Molnár J, Hohmann J. Alkaloids from Leucojum vernum and antiretroviral activity of amaryllidaceae alkaloids. Planta Med. 2004. 70(9):871–3.
  • 16. Zhang Y-N, Zhang Q-Y, Li X-D, Xiong J, Xiao S-Q, Wang Z, et al. Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture. Emerg Microbes Infect. 2020.
  • 17. He J, Qi WB, Wang L, Tian J, Jiao PR, Liu GQ, et al. Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1. Influenza Other Respi Viruses. 2013. 7(6):922–31.
  • 18. Yang L, Zhang JH, Zhang XL, Lao GJ, Su GM, Wang L, et al. Tandem mass tag-based quantitative proteomic analysis of lycorine treatment in highly pathogenic avian influenza H5N1 virus infection. PeerJ. 2019. 2019(10):1–23.
  • 19. Liu J, Yang Y, Xu Y, Ma C, Qin C, Zhang L. Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication. Virol J 2011,. 2011. 8(483):1–9.
  • 20. Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 2005. 67(1):18–23.
  • 21. Jin Y, Sun J, Jeon S, Lee J, Kim S, Rae H, et al. Lycorine, a non-nucleoside RNA dependent RNA polymerase inhibitor, as potential treatment for emerging coronavirus infections. 2020. (January).
  • 22. Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. 2020.
  • 23. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera -- A visualization system for exploratory research and analysis. J Comput Chem [Internet]. 2004 Oct. 25(13):1605–12. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jcc.20084
  • 24. Morris GM, Ruth H, WILLIAM LINDSTROM, SANNER MF, BELEW RK, GOODSELL DS, et al. AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J Comput Chem. 2009. 30:2785–91.
  • 25. Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, et al. General atomic and molecular electronic structure system. J Comput Chem. 1993 Nov. 14(11):1347–63.
  • 26. Pritchard BP, Altarawy D, Didier B, Gibson TD, Windus TL. New Basis Set Exchange: An Open, Up-to-Date Resource for the Molecular Sciences Community. J Chem Inf Model. 2019. 59(11):4814–20.
  • 27. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009 Dec. 30(16):2785–91.
  • 28. BIOVIA DS. Discovery Studio Visualiser. San Diego: Dassault Systèmes D.S. BIOVIA. 2019.
  • 29. Nguyen MN, Tan KP, Madhusudhan MS. CLICK - Topology-independent comparison of biomolecular 3D structures. Nucleic Acids Res. 2011. 39(SUPPL. 2):24–8.
  • 30. Case DA, Cerutti DS, Cheatham TEI, Darden TA, Duke RE, Giese TJ, et al. Amber 2017 reference manual. Univ California, San Fr. 2017. AMBER 2017, University of California, San Francisc.
  • 31. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. Development and testing of a general amber force field. J Comput Chem. 2004 Jul. 25(9):1157–74.
  • 32. Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C. ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J Chem Theory Comput. 2015 Aug. 11(8):3696–713.
  • 33. Hopkins CW, Le Grand S, Walker RC, Roitberg AE. Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning. J Chem Theory Comput [Internet]. 2015 Apr 14. 11(4):1864–74. Available from: https://pubs.acs.org/doi/10.1021/ct5010406
  • 34. Miller BR, McGee TD, Swails JM, Homeyer N, Gohlke H, Roitberg AE. MMPBSA.py : An Efficient Program for End-State Free Energy Calculations. J Chem Theory Comput [Internet]. 2012 Sep 11. 8(9):3314–21. Available from: https://pubs.acs.org/doi/10.1021/ct300418h
  • 35. Roe DR, Cheatham TE. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J Chem Theory Comput [Internet]. 2013 Jul 9. 9(7):3084–95. Available from: https://pubs.acs.org/doi/10.1021/ct400341p
  • 36. Sharp KA, Honig B. Calculating total electrostatic energies with the nonlinear Poisson-Boltzmann equation. J Phys Chem [Internet]. 1990 Sep 1. 94(19):7684–92. Available from: https://pubs.acs.org/doi/10.1021/j100382a068
  • 37. Tsui V, Case DA. Theory and applications of the Generalized Born solvation model in macromolecular simulations. Biopolymers [Internet]. 2000. 56(4):275–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11754341
  • 38. Hou T, Wang J, Li Y, Wang W. Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations. J Chem Inf Model [Internet]. 2011 Jan 24. 51(1):69–82. Available from: https://pubs.acs.org/doi/10.1021/ci100275a
  • 39. Murugesan S, Kottekad S, Crasta I, Sreevathsan S, Usharani D, Perumal MK, et al. Targeting COVID-19 (SARS-CoV-2) main protease through active phytocompounds of ayurvedic medicinal plants – Emblica officinalis (Amla), Phyllanthus niruri Linn. (Bhumi Amla) and Tinospora cordifolia (Giloy) – A molecular docking and simulation study. Comput Biol Med [Internet]. 2021 Sep. 136:104683. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0010482521004777
  • 40. Enmozhi SK, Raja K, Sebastine I, Joseph J. Andrographolide As a Potential Inhibitor of SARS-CoV-2 Main Protease: An In Silico Approach. J Biomol Struct Dyn. 2020. 0(0):1–10.
  • 41. Sen Gupta PS, Biswal S, Panda SK, Ray AK, Rana MK. Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α with in-vitro effective drug ivermectin. J Biomol Struct Dyn [Internet]. 2020 Oct 28. 1–10. Available from: https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1839564
  • 42. Bera K. Binding and inhibitory effect of ravidasvir on 3CL pro of SARS-CoV‐2: a molecular docking, molecular dynamics and MM/PBSA approach. J Biomol Struct Dyn [Internet]. 2021 Mar 8. 1–8. Available from: https://www.tandfonline.com/doi/full/10.1080/07391102.2021.1896388

Year 2022, Volume: 5 Issue: 3, 424 - 435, 15.12.2022

Barış Kurt

https://doi.org/10.38001/ijlsb.1110761
Cited By: 3

Abstract

References

  • 1. Weiss SR, Navas-Martin S. Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus. Microbiol Mol Biol Rev. 2005. 69(4):635–64.
  • 2. Ji W, Wang W, Zhao X, Zai J, Li X. Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol. 2020.
  • 3. Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomed. 2020. 91(1):157–60.
  • 4. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020. 579(7798):265–9.
  • 5. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019. 17(3):181–92.
  • 6. Zhou P, Yang X Lou, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020. 579(7798):270–3.
  • 7. Ghosh AK, Xi K, Ratia K, Santarsiero BD, Fu W, Harcourt BH, et al. Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors. J Med Chem. 2005 Nov. 48(22):6767–71.
  • 8. Dömling A, Gao L. Chemistry and Biology of SARS-CoV-2. Chem. 2020. 6(6):1283–95.
  • 9. Needle D, Lountos GT, Waugh DS. Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity. Acta Crystallogr Sect D Biol Crystallogr. 2015. 71:1102–11.
  • 10. Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. ( 3CL pro ) Structure : Basis for Design of Anti-SARS Drugs. Science (80- ). 2003. 300(June):1763–7.
  • 11. Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen LL. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020. (xxxx):1–7.
  • 12. Callaway E. Beyond Omicron: what’s next for COVID’s viral evolution. Nature. 2021. 600(7888):204–7.
  • 13. Shen JW, Ruan Y, Ren W, Ma BJ, Wang XL, Zheng CF. Lycorine: A potential broad-spectrum agent against crop pathogenic fungi. J Microbiol Biotechnol. 2014. 24(3):354–8.
  • 14. Shawky E. In-silico profiling of the biological activities of Amaryllidaceae alkaloids. J Pharm Pharmacol. 2017. 69(11):1592–605.
  • 15. Szlávik L, Gyuris Á, Minárovits J, Forgo P, Molnár J, Hohmann J. Alkaloids from Leucojum vernum and antiretroviral activity of amaryllidaceae alkaloids. Planta Med. 2004. 70(9):871–3.
  • 16. Zhang Y-N, Zhang Q-Y, Li X-D, Xiong J, Xiao S-Q, Wang Z, et al. Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture. Emerg Microbes Infect. 2020.
  • 17. He J, Qi WB, Wang L, Tian J, Jiao PR, Liu GQ, et al. Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1. Influenza Other Respi Viruses. 2013. 7(6):922–31.
  • 18. Yang L, Zhang JH, Zhang XL, Lao GJ, Su GM, Wang L, et al. Tandem mass tag-based quantitative proteomic analysis of lycorine treatment in highly pathogenic avian influenza H5N1 virus infection. PeerJ. 2019. 2019(10):1–23.
  • 19. Liu J, Yang Y, Xu Y, Ma C, Qin C, Zhang L. Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication. Virol J 2011,. 2011. 8(483):1–9.
  • 20. Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 2005. 67(1):18–23.
  • 21. Jin Y, Sun J, Jeon S, Lee J, Kim S, Rae H, et al. Lycorine, a non-nucleoside RNA dependent RNA polymerase inhibitor, as potential treatment for emerging coronavirus infections. 2020. (January).
  • 22. Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. 2020.
  • 23. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera -- A visualization system for exploratory research and analysis. J Comput Chem [Internet]. 2004 Oct. 25(13):1605–12. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jcc.20084
  • 24. Morris GM, Ruth H, WILLIAM LINDSTROM, SANNER MF, BELEW RK, GOODSELL DS, et al. AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J Comput Chem. 2009. 30:2785–91.
  • 25. Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, et al. General atomic and molecular electronic structure system. J Comput Chem. 1993 Nov. 14(11):1347–63.
  • 26. Pritchard BP, Altarawy D, Didier B, Gibson TD, Windus TL. New Basis Set Exchange: An Open, Up-to-Date Resource for the Molecular Sciences Community. J Chem Inf Model. 2019. 59(11):4814–20.
  • 27. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009 Dec. 30(16):2785–91.
  • 28. BIOVIA DS. Discovery Studio Visualiser. San Diego: Dassault Systèmes D.S. BIOVIA. 2019.
  • 29. Nguyen MN, Tan KP, Madhusudhan MS. CLICK - Topology-independent comparison of biomolecular 3D structures. Nucleic Acids Res. 2011. 39(SUPPL. 2):24–8.
  • 30. Case DA, Cerutti DS, Cheatham TEI, Darden TA, Duke RE, Giese TJ, et al. Amber 2017 reference manual. Univ California, San Fr. 2017. AMBER 2017, University of California, San Francisc.
  • 31. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. Development and testing of a general amber force field. J Comput Chem. 2004 Jul. 25(9):1157–74.
  • 32. Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C. ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J Chem Theory Comput. 2015 Aug. 11(8):3696–713.
  • 33. Hopkins CW, Le Grand S, Walker RC, Roitberg AE. Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning. J Chem Theory Comput [Internet]. 2015 Apr 14. 11(4):1864–74. Available from: https://pubs.acs.org/doi/10.1021/ct5010406
  • 34. Miller BR, McGee TD, Swails JM, Homeyer N, Gohlke H, Roitberg AE. MMPBSA.py : An Efficient Program for End-State Free Energy Calculations. J Chem Theory Comput [Internet]. 2012 Sep 11. 8(9):3314–21. Available from: https://pubs.acs.org/doi/10.1021/ct300418h
  • 35. Roe DR, Cheatham TE. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J Chem Theory Comput [Internet]. 2013 Jul 9. 9(7):3084–95. Available from: https://pubs.acs.org/doi/10.1021/ct400341p
  • 36. Sharp KA, Honig B. Calculating total electrostatic energies with the nonlinear Poisson-Boltzmann equation. J Phys Chem [Internet]. 1990 Sep 1. 94(19):7684–92. Available from: https://pubs.acs.org/doi/10.1021/j100382a068
  • 37. Tsui V, Case DA. Theory and applications of the Generalized Born solvation model in macromolecular simulations. Biopolymers [Internet]. 2000. 56(4):275–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11754341
  • 38. Hou T, Wang J, Li Y, Wang W. Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations. J Chem Inf Model [Internet]. 2011 Jan 24. 51(1):69–82. Available from: https://pubs.acs.org/doi/10.1021/ci100275a
  • 39. Murugesan S, Kottekad S, Crasta I, Sreevathsan S, Usharani D, Perumal MK, et al. Targeting COVID-19 (SARS-CoV-2) main protease through active phytocompounds of ayurvedic medicinal plants – Emblica officinalis (Amla), Phyllanthus niruri Linn. (Bhumi Amla) and Tinospora cordifolia (Giloy) – A molecular docking and simulation study. Comput Biol Med [Internet]. 2021 Sep. 136:104683. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0010482521004777
  • 40. Enmozhi SK, Raja K, Sebastine I, Joseph J. Andrographolide As a Potential Inhibitor of SARS-CoV-2 Main Protease: An In Silico Approach. J Biomol Struct Dyn. 2020. 0(0):1–10.
  • 41. Sen Gupta PS, Biswal S, Panda SK, Ray AK, Rana MK. Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α with in-vitro effective drug ivermectin. J Biomol Struct Dyn [Internet]. 2020 Oct 28. 1–10. Available from: https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1839564
  • 42. Bera K. Binding and inhibitory effect of ravidasvir on 3CL pro of SARS-CoV‐2: a molecular docking, molecular dynamics and MM/PBSA approach. J Biomol Struct Dyn [Internet]. 2021 Mar 8. 1–8. Available from: https://www.tandfonline.com/doi/full/10.1080/07391102.2021.1896388
There are 42 citations in total.

Details

Primary Language English
Subjects Chemical Engineering
Journal Section Research Articles
Authors

Barış Kurt 0000-0002-1406-0915

Early Pub Date May 14, 2022
Publication Date December 15, 2022
Published in Issue Year 2022 Volume: 5 Issue: 3

Cite

EndNote Kurt B (December 1, 2022) Investigation of The Potential Inhibitor Effects Of Lycorine On Sars-Cov-2 Main Protease (Mpro) Using Molecular Dynamics Simulations and MMPBSA. International Journal of Life Sciences and Biotechnology 5 3 424–435.

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