In-silico study MM/GBSA binding free energy and molecular dynamics simulation of some designed remdesivir derivatives as the inhibitory potential of SARS-CoV-2 main protease

Maryam Abbasi, Mahboubeh Mansourian, Afsaneh Arefi Oskouie , Salman Taheri, Karim Mahnam

Abstract


Background and purpose: Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed.

Experimental approach: The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study.

Findings/Results: The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 Å, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding.

Conclusion and implications: Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.

 

 


Keywords


3CLpro; Main protease; MM-GBSA; Molecular docking; Molecular dynamics simulation; Remdesivir.

Full Text:

PDF

References


Kahn JS, McIntosh K. History and recent advances in coronavirus discovery. Pediatr Infect Dis J. 2005;24(11 Suppl):S223-S226.DOI: 10.1097/01.inf.0000188166.17324.60.

Jones DS. History in a crisis - lessons for Covid-19. N Engl J Med. 2020;382(18):1681-1683. DOI: 10.1056/NEJMp2004361.

World Health Organization, WHO Health Emergencies Programme, WHO COVID-19 dashboard. Available on: https://covid19.who.int/

Nadeem MS, Zamzami MA, Choudhry H, Murtaza BN, Kazmi I, Ahmad H, et al. Origin, potential therapeutic targets and treatment for coronavirus disease (COVID-19). Pathogens. 2020;9(4):307,1-13. DOI: 10.3390/pathogens9040307.

Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7):e00127-20,1-25.DOI: 10.1128/JVI.00127-20.

Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381-385.DOI: 10.1038/nature17180.

Santos R, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. J Endocrinol. 2013;216(2):R1-R17.DOI: 10.1530/joe-12-0341.

Zhang DH, Wu KL, Zhang X, Deng SQ, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med. 2020;18(2):152-158.DOI: 10.1016/j.joim.2020.02.005.

Freitas BT, Durie I A, Murray J, Longo J E, Miller HC, et al. Characterization and noncovalent inhibition of the deubiquitinase and deISGylase activity of SARS-CoV-2 papain-like protease. ACS Infect Dis. 2020;6(8):2099-2109.DOI: 10.1021/acsinfecdis.0c00168.

Naik VR, Munikumar M, Ramakrishna U, Srujana M, Goudar G, Naresh P, et al. Remdesivir (GS-5734) as a therapeutic option of 2019-nCOV main protease-in silico approach. J Biomol Struct Dyn. 2021;39(13):4701-4714.DOI: 10.1080/07391102.2020.1781694.

Liu C, Zhou Q, Li Y, Garner LV, Watkins SP, Carter LJ, et al. Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent Sci. 2020;6(3):315-331.DOI: 10.1021/acscentsci.0c00272.

Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409-412.DOI: 10.1126/science.abb3405.

Koulgi S, Jani V, Uppuladinne M, Sonavane U, Nath AK, Darbari H, et al. Drug repurposing studies targeting SARS-CoV-2: an ensemble docking approach on drug target 3C-like protease (3CLpro). J Biomol Struct Dyn. 2021;39(15):5735-5755.DOI: 10.1080/07391102.2020.1792344.

Nguyen HL, Thai NQ, Truong DT, Li MS. Remdesivir strongly binds to both RNA-dependent RNA polymerase and main protease of SARS-CoV-2: evidence from molecular simulations. J Phys Chem B. 2020;124(50):11337-11348.DOI: 10.1021/acs.jpcb.0c07312.

Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of M pro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582(7811):289-293.DOI: 10.1038/s41586-020-2223-y.

Xue X, Yu H, Yang H, Xue F, Wu Z, Shen W, et al. Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design. J Virol. 2008;82(5):2515-2527.DOI: 10.1128/JVI.02114-07.

Wang F, Chen C, Tan W, Yang K, Yang H. Structure of main protease from human coronavirus NL63: insights for wide spectrum anti-coronavirus drug design. Sci Rep. 2016;6(1):22677,1-12. DOI: 10.1038/srep22677.

Vardhan S, Sahoo SK. In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoids for COVID-19. Comput Biol Med. 2020;124:103936,1-12. DOI: 10.1016/j.compbiomed.2020.103936.

Muralidharan N, Sakthivel R, Velmurugan D, Gromiha MM. Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 protease against COVID-19. J Biomol Struct Dyn. 2021;39(7):2673-2678.DOI: 10.1080/07391102.2020.1752802.

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787-1799.DOI: 10.1056/NEJMoa2001282.

Stower H. Lopinavir-ritonavir in severe COVID-19. Nat Med. 2020;26(4):465,1-2.DOI: 10.1038/s41591-020-0849-9.

Akhtar MJ. COVID19 inhibitors: a prospective therapeutics. Bioorg Chem. 2020;101:104027,1-26.DOI: 10.1016/j.bioorg.2020.104027.

Siordia JA, Bernaba M, Yoshino K, Ulhaque A, Kumar S, Bernaba M, et al. Systematic and statistical review of COVID19 treatment trials. SN Compr Clin Med. 2020;2(8):1120-1131.DOI: 10.1007/s42399-020-00399-6.

Khalili JS, Zhu H, Mak NSA, Yan Y, Zhu Y. Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID‐19. J Med Virol,. 2020 ;92(7):740-746.DOI: 10.1002/jmv.25798.

Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020;177:104762,1-2.DOI: 10.1016/j.antiviral.2020.104762.

Pagliano P, Piazza O, De Caro F, Ascione T, Filippelli A. Is hydroxychloroquine a possible post-exposure prophylaxis drug to limit the transmission to health care workers exposed to COVID19. Clin Infect Dis. 2020;71(15):887-888.DOI: 10.1093/cid/ciaa320.

Uno Y. Camostat mesilate therapy for COVID-19. Intern Emerg Med. 2020;15(8):1577-1578.DOI: 10.1007/s11739-020-02345-9.

Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L, et al. Effect of dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-704.DOI: 10.1056/NEJMoa2021436.

Wang Y, Anirudhan V, Du R, Cui Q, Rong L. RNA‐dependent RNA polymerase of SARS‐CoV‐2 as a therapeutic target. J Med Virol. 2021;93(1):300-310.DOI: 10.1002/jmv.26264.

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.DOI: 10.1038/s41422-020-0282-0.

FDA Approves First Treatment for COVID-19. Available on: https://wwwfdagov/news-events/press-announcements/fda-approves-first-treatment-covid-19. 2020.

Consortium WST. Repurposed antiviral drugs for COVID-19-interim WHO solidarity trial results. N Engl J Med. 2021;384(6):497-511.DOI: 10.1056/NEJMoa2023184.

Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen HS, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740-746.DOI: 10.1038/s41594-021-00651-0.

Khan SA, Zia K, Ashraf S, Uddin R, Ul-Haq Z. Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach. J Biomol Struct Dyn. 2021;39(7):2607-2616.DOI: 10.1080/07391102.2020.1751298.

Mishra A, Rathore AS. RNA dependent RNA polymerase (RdRp) as a drug target for SARS-CoV2. J Biomol Struct Dyn. 2022;40(13):6039-6051.DOI: 10.1080/07391102.2021.1875886.

Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582(7811):289-293.DOI: 10.1038/s41586-020-2223-y.

Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013;27(3):221-234.DOI: 10.1007/s10822-013-9644-8.

Schrödinger Release 2023-2: LigPrep, Schrödinger, LLC, New York, NY, 2021.

Kramer C, Ting A, Zheng H, Hert J, Schindler T,Stahl M, et al. Learning medicinal chemistry absorption, distribution, metabolism, excretion, and toxicity (ADMET) rules from cross-company matched molecular pairs analysis (MMPA). J Med Chem. 2018,61(8):3277-3292.DOI: 10.1021/acs.jmedchem.7b00935.

Lagorce D, Douguet D, Miteva M, Villoutreix B. Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors. Sci Rep. 2017;7:46277,1-15.DOI: 10.1038/srep46277.

Schrodinger L. Glide, Version 6.6. New York (NY). 2015.

Abbasi M, Sadeghi-Aliabadi H. An in-silico screening strategy to the prediction of new inhibitors of COVID-19 Mpro protein. Iran J Pharm Res. 2021;20(4):125-136.DOI: 10.22037/ijpr.2021.114997.15146.

Lokhande KB, Doiphode S, Vyas R, Swamy KV. Molecular docking and simulation studies on SARS-CoV-2 Mpro reveals mitoxantrone, leucovorin, birinapant, and dynasore as potent drugs against COVID-19. J Biomol Struct Dyn. 2021;39(18): 7294-7305.DOI: 10.1080/07391102.2020.1805019.

Pearlman DA, Charifson PS. Are free energy calculations useful in practice? A comparison with rapid scoring functions for the p38 MAP kinase protein system. J Med Chem. 2001;44(21):3417-3423.DOI: 10.1021/jm0100279.

Huang N, Kalyanaraman C, Irwin JJ, Jacobson MP. Physics-based scoring of protein-ligand complexes: Enrichment of known inhibitors in large-scale virtual screening. J Chem Inf Model. 2006;46(1):243-253.DOI: 10.1021/ci0502855.

Mulakala C, Viswanadhan V. Could MM-GBSA be accurate enough for calculation of absolute protein/ligand binding free energies? J Mol Graph Model. 2013;46:41-51.DOI: 10.1016/j.jmgm.2013.09.005.

Mansourian M, Mahnam K, Rajabi HR, Roushani M, Doustimotlagh AH. Exploring the binding mechanism of saccharin and sodium saccharin to promoter of human p53 gene by theoretical and experimental methods. J Biomol Struct Dyn. 2020;38(2):548-564.DOI: 10.1080/07391102.2019.1582438.

Hess B, Kutzner C, Van Der Spoel D, Lindahl E. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput. 2008;4(3):435-447.

Theory Comput. 2008;4(3):435-447.DOI: 10.1021/ct700301q.

Nasab RR, Mansourian M, Hassanzadeh F, Shahlaei M. Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in-silico and in-vitro cytotoxicity methods. Res Pharm Sci. 2018;13(6):509-522.DOI: 10.4103/1735-5362.245963.

Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1:19-25.DOI: 10.1016/j.softx.2015.06.001.

da Silva AWS, Vranken WF. ACPYPE-antechamber python parser interface. BMC Res Notes. 2012;5:367,1-8.DOI: 10.1186/1756-0500-5-367.

Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79(2):926-935.DOI: 10.1063/1.445869.

Hess B, Bekker H, Berendsen HJ, Fraaije JG. LINCS: a linear constraint solver for molecular simulations. J Comput Chem. 1997;18(12):1463-72.DOI: 10.1002/(SICI)1096-987X(199709)18:12< 1463::AID-JCC4>3.0.CO;2-H.

Darden T, York D, Pedersen L. Particle mesh Ewald: an N⋅log (N) method for Ewald sums in large systems. J Chem Phys. 1993;98(12):10089-10092.DOI: 10.1063/1.464397.

Berendsen HJ, Postma JV, van Gunsteren WF, DiNola A, Haak JR. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81(8):3684-3690.DOI: 10.1063/1.448118.

Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33-38.DOI: 10.1016/0263-7855(96)00018-5.

Makarewicz T, Kazmierkiewicz R. Molecular dynamics simulation by GROMACS using GUI plugin for PyMOL. J Chem Inf Model. 2013;53(5):1229-1234.DOI: 10.1021/ci400071x.

Sirous H, Chemi G, Campiani G, Brogi S. An integrated in silico screening strategy for identifying promising disruptors of p53-MDM2 interaction. Comput Biol Chem. 2019;83:107105,1-61.DOI: 10.1016/j.compbiolchem.2019.107105.

Razzaghi-Asl N, Mirzayi S, Mahnam K, Adhami V, Sepehri S. In silico screening and molecular dynamics simulations toward new human papillomavirus 16 type inhibitors. Res Pharm Sci. 2022;17(2):189-208. DOI: 10.4103/1735-5362.335177.

Yazdani M, Khezri J, Hadizadeh N, Zamani Amir Zakaria J, Naderi M, Mahmoodian S, et al. Depinar, a drug that potentially inhibits the binding and entry of COVID-19 into host cells based on computer-aided studies. Res Pharm Sci. 2021;16(3):315-325. DOI: 10.4103/1735-5362.314830.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.