Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Remdesivir: Mechanism of Metabolic Conversion from Prodrug to Drug

Author(s): Saumya Kapoor, Gurudutt Dubey, Samima Khatun and Prasad V. Bharatam*

Volume 23, Issue 1, 2022

Published on: 21 January, 2022

Page: [73 - 81] Pages: 9

DOI: 10.2174/1389200223666211228160314

Price: $65

Abstract

Background: Remdesivir (GS-5734) has emerged as a promising drug during the challenging times of COVID-19 pandemic. Being a prodrug, it undergoes several metabolic reactions before converting to its active triphosphate metabolite. It is important to establish the atomic level details and explore the energy profile of the prodrug to drug conversion process.

Methods: In this work, Density Functional Theory (DFT) calculations were performed to explore the entire metabolic path. Further, the potential energy surface (PES) diagram for the conversion of prodrug remdesivir to its active metabolite was established. The role of catalytic triad of Hint1 phosphoramidase enzyme in P-N bond hydrolysis was also studied on a model system using combined molecular docking and quantum mechanics approach.

Results: The overall energy of reaction is 11.47 kcal/mol exergonic and the reaction proceeds through many steps requiring high activation energies. In the absence of a catalyst, the P-N bond breaking step requires 41.78 kcal/mol, which is reduced to 14.26 kcal/mol in a catalytic environment.

Conclusion: The metabolic pathways of model system of remdesivir (MSR) were explored completely and potential energy surface diagrams at two levels of theory, B3LYP/6-311++G(d, p) and B3LYP/6-31+G(d), were established and compared. The results highlight the importance of an additional water molecule in the metabolic reaction. The PN bond cleavage step of the metabolic process requires the presence of an enzymatic environment.

Keywords: Remdesivir, GS-5734, metabolism, density functional theory, COVID-19, prodrug.

« Previous Next »
Graphical Abstract

[1]
Warren, T.K.; Jordan, R.; Lo, M.K.; Ray, A.S.; Mackman, R.L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H.C.; Larson, N.; Strickley, R.; Wells, J.; Stuthman, K.S.; Van Tongeren, S.A.; Garza, N.L.; Donnelly, G.; Shurtleff, A.C.; Retterer, C.J.; Gharaibeh, D.; Zamani, R.; Kenny, T.; Eaton, B.P.; Grimes, E.; Welch, L.S.; Gomba, L.; Wilhelmsen, C.L.; Nichols, D.K.; Nuss, J.E.; Nagle, E.R.; Kugelman, J.R.; Palacios, G.; Doerffler, E.; Neville, S.; Carra, E.; Clarke, M.O.; Zhang, L.; Lew, W.; Ross, B.; Wang, Q.; Chun, K.; Wolfe, L.; Babusis, D.; Park, Y.; Stray, K.M.; Trancheva, I.; Feng, J.Y.; Barauskas, O.; Xu, Y.; Wong, P.; Braun, M.R.; Flint, M.; McMullan, L.K.; Chen, S.S.; Fearns, R.; Swaminathan, S.; Mayers, D.L.; Spiropoulou, C.F.; Lee, W.A.; Nichol, S.T.; Cihlar, T.; Bavari, S. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature, 2016, 531(7594), 381-385.
[http://dx.doi.org/10.1038/nature17180] [PMID: 26934220]
[2]
Beigel, J.H.; Tomashek, K.M.; Dodd, L.E.; Mehta, A.K.; Zingman, B.S.; Kalil, A.C.; Hohmann, E.; Chu, H.Y.; Luetkemeyer, A.; Kline, S.; Lopez de Castilla, D.; Finberg, R.W.; Dierberg, K.; Tapson, V.; Hsieh, L.; Patterson, T.F.; Paredes, R.; Sweeney, D.A.; Short, W.R.; Touloumi, G.; Lye, D.C.; Ohmagari, N.; Oh, M.D.; Ruiz-Palacios, G.M.; Benfield, T.; Fätkenheuer, G.; Kortepeter, M.G.; Atmar, R.L.; Creech, C.B.; Lundgren, J.; Babiker, A.G.; Pett, S.; Neaton, J.D.; Burgess, T.H.; Bonnett, T.; Green, M.; Makowski, M.; Osinusi, A.; Nayak, S.; Lane, H.C. ACTT-1 Study Group Members. Remdesivir for the treatment of covid-19 - final report. N. Engl. J. Med., 2020, 383(19), 1813-1826.
[http://dx.doi.org/10.1056/NEJMoa2007764] [PMID: 32445440]
[3]
Williamson, B.N.; Feldmann, F.; Schwarz, B.; Meade-White, K.; Porter, D.P.; Schulz, J.; van Doremalen, N.; Leighton, I.; Yinda, C.K.; Pérez-Pérez, L.; Okumura, A.; Lovaglio, J.; Hanley, P.W.; Saturday, G.; Bosio, C.M.; Anzick, S.; Barbian, K.; Cihlar, T.; Martens, C.; Scott, D.P.; Munster, V.J.; de Wit, E. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature, 2020, 585(7824), 273-276.
[http://dx.doi.org/10.1038/s41586-020-2423-5] [PMID: 32516797]
[4]
Wang, Y.; Zhang, D.; Du, G.; Du, R.; Zhao, J.; Jin, Y.; Fu, S.; Gao, L.; Cheng, Z.; Lu, Q.; Hu, Y.; Luo, G.; Wang, K.; Lu, Y.; Li, H.; Wang, S.; Ruan, S.; Yang, C.; Mei, C.; Wang, Y.; Ding, D.; Wu, F.; Tang, X.; Ye, X.; Ye, Y.; Liu, B.; Yang, J.; Yin, W.; Wang, A.; Fan, G.; Zhou, F.; Liu, Z.; Gu, X.; Xu, J.; Shang, L.; Zhang, Y.; Cao, L.; Guo, T.; Wan, Y.; Qin, H.; Jiang, Y.; Jaki, T.; Hayden, F.G.; Horby, P.W.; Cao, B.; Wang, C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 2020, 395(10236), 1569-1578.
[http://dx.doi.org/10.1016/S0140-6736(20)31022-9] [PMID: 32423584]
[5]
Pan, H.; Peto, R.; Henao-Restrepo, A.M.; Preziosi, M.P.; Sathiyamoorthy, V.; Abdool Karim, Q.; Alejandria, M.M.; Hernández García, C.; Kieny, M.P.; Malekzadeh, R.; Murthy, S.; Reddy, K.S.; Roses Periago, M.; Abi Hanna, P.; Ader, F.; Al-Bader, A.M.; Alhasawi, A.; Allum, E.; Alotaibi, A.; Alvarez-Moreno, C.A.; Appadoo, S.; Asiri, A.; Aukrust, P.; Barratt-Due, A.; Bellani, S.; Branca, M.; Cappel-Porter, H.B.C.; Cerrato, N.; Chow, T.S.; Como, N.; Eustace, J.; García, P.J.; Godbole, S.; Gotuzzo, E.; Griskevicius, L.; Hamra, R.; Hassan, M.; Hassany, M.; Hutton, D.; Irmansyah, I.; Jancoriene, L.; Kirwan, J.; Kumar, S.; Lennon, P.; Lopardo, G.; Lydon, P.; Magrini, N.; Maguire, T.; Manevska, S.; Manuel, O.; McGinty, S.; Medina, M.T.; Mesa Rubio, M.L.; Miranda-Montoya, M.C. Nel, J.; Nunes, E.P.; Perola, M.; Portolés, A.; Rasmin, M.R.; Raza, A.; Rees, H.; Reges, P.P.S.; Rogers, C.A.; Salami, K.; Salvadori, M.I.; Sinani, N.; Sterne, J.A.C.; Stevanovikj, M.; Tacconelli, E.; Tikkinen, K.A.O.; Trelle, S.; Zaid, H.; Røttingen, J.A.; Swaminathan, S. WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results. N. Engl. J. Med., 2021, 384(6), 497-511.
[http://dx.doi.org/10.1056/NEJMoa2023184] [PMID: 33264556]
[6]
Siegel, D.; Hui, H.C.; Doerffler, E.; Clarke, M.O.; Chun, K.; Zhang, L.; Neville, S.; Carra, E.; Lew, W.; Ross, B.; Wang, Q.; Wolfe, L.; Jordan, R.; Soloveva, V.; Knox, J.; Perry, J.; Perron, M.; Stray, K.M.; Barauskas, O.; Feng, J.Y.; Xu, Y.; Lee, G.; Rheingold, A.L.; Ray, A.S.; Bannister, R.; Strickley, R.; Swaminathan, S.; Lee, W.A.; Bavari, S.; Cihlar, T.; Lo, M.K.; Warren, T.K.; Mackman, R.L. Discovery and synthesis of a phosphoramidate prodrug of a Pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of ebola and emerging viruses. J. Med. Chem., 2017, 60(5), 1648-1661.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01594] [PMID: 28124907]
[7]
Gordon, C.J.; Tchesnokov, E.P.; Woolner, E.; Perry, J.K.; Feng, J.Y.; Porter, D.P.; Götte, M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J. Biol. Chem., 2020, 295(20), 6785-6797.
[http://dx.doi.org/10.1074/jbc.RA120.013679] [PMID: 32284326]
[8]
Mehellou, Y.; Balzarini, J.; McGuigan, C. Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells. ChemMedChem, 2009, 4(11), 1779-1791.
[http://dx.doi.org/10.1002/cmdc.200900289] [PMID: 19760699]
[9]
Mehellou, Y.; Rattan, H.S.; Balzarini, J. The protide prodrug technology: from the concept to the clinic. J. Med. Chem., 2018, 61(6), 2211-2226.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00734] [PMID: 28792763]
[10]
Slusarczyk, M.; Serpi, M.; Pertusati, F. Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antivir. Chem. Chemother., 2018, 262040206618775243
[http://dx.doi.org/10.1177/2040206618775243] [PMID: 29792071]
[11]
Saboulard, D.; Naesens, L.; Cahard, D.; Salgado, A.; Pathirana, R.; Velazquez, S.; McGuigan, C.; De Clercq, E.; Balzarini, J. Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. Mol. Pharmacol., 1999, 56(4), 693-704.
[PMID: 10496951]
[12]
Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H.M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A.M.; Otto, M.J.; Sofia, M.J.; Furman, P.A.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H.M.M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A.M.; Otto, M.J.; Sofia, M.J.; Furman, P.A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem., 2010, 285(45), 34337-34347.
[http://dx.doi.org/10.1074/jbc.M110.161802] [PMID: 20801890]
[13]
Birkus, G.; Wang, R.; Liu, X.; Kutty, N.; Macarthur, H.; Cihlar, T.; Gibbs, C.; Swaminathan, S.; Lee, W.; Mcdermott, M. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate., 2007, 51, 543-550.
[14]
Congiatu, C.; Brancale, A.; McGuigan, C. Molecular modelling studies on the binding of some protides to the putative human phosphoramidase Hint1. Nucleosides Nucleotides Nucleic Acids, 2007, 26(8-9), 1121-1124.
[http://dx.doi.org/10.1080/15257770701521656] [PMID: 18058549]
[15]
Yan, V.C.; Muller, F.L. Advantages of the parent nucleoside GS-441524 over remdesivir for Covid-19 treatment. ACS Med. Chem. Lett., 2020, 11(7), 1361-1366.
[http://dx.doi.org/10.1021/acsmedchemlett.0c00316] [PMID: 32665809]
[16]
Adelfinskaya, O.; Herdewijn, P. Amino acid phosphoramidate nucleotides as alternative substrates for HIV-1 reverse transcriptase. Angew. Chem. Int. Ed., 2007, 46(23), 4356-4358.
[http://dx.doi.org/10.1002/anie.200605016] [PMID: 17443759]
[17]
Maiti, M.; Michielssens, S.; Dyubankova, N.; Maiti, M.; Lescrinier, E.; Ceulemans, A.; Herdewijn, P. Influence of the nucleobase and anchimeric assistance of the carboxyl acid groups in the hydrolysis of amino acid nucleoside phosphoramidates. Chemistry, 2012, 18(3), 857-868.
[http://dx.doi.org/10.1002/chem.201102279] [PMID: 22173724]
[18]
Eastman, R.T.; Roth, J.S.; Brimacombe, K.R.; Simeonov, A.; Shen, M.; Patnaik, S.; Hall, M.D. Remdesivir: a review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent. Sci., 2020, 6(5), 672-683.
[http://dx.doi.org/10.1021/acscentsci.0c00489] [PMID: 32483554]
[19]
Zhang, L.; Zhou, R. Structural basis of the potential binding mechanism of remdesivir to SARS-CoV-2 RNA-dependent RNA polymerase. J. Phys. Chem. B, 2020, 124(32), 6955-6962.
[http://dx.doi.org/10.1021/acs.jpcb.0c04198] [PMID: 32521159]
[20]
Jung, L.S.; Gund, T.M.; Narayan, M. Comparison of binding site of remdesivir and its metabolites with NSP12-NSP7-NSP8, and NSP3 of SARS CoV-2 virus and alternative potential drugs for COVID-19 treatment. Protein J., 2020, 39(6), 619-630.
[http://dx.doi.org/10.1007/s10930-020-09942-9] [PMID: 33185784]
[21]
Wang, J.; Reiss, K.; Shi, Y.; Lolis, E.; Lisi, G.P.; Batista, V.S. Mechanism of inhibition of the reproduction of SARS-CoV-2 and Ebola viruses by remdesivir. Biochemistry, 2021, 60(24), 1869-1875.
[http://dx.doi.org/10.1021/acs.biochem.1c00292] [PMID: 34110129]
[22]
Byléhn, F.; Menéndez, C.A.; Perez-Lemus, G.R.; Alvarado, W.; de Pablo, J.J. Modeling the binding mechanism of remdesivir, favilavir, and ribavirin to SARS-CoV-2 RNA-dependent RNA polymerase. ACS Cent. Sci., 2021, 7(1), 164-174.
[http://dx.doi.org/10.1021/acscentsci.0c01242] [PMID: 33527086]
[23]
Ricci, A.; Brancale, A. Density functional theory calculation of cyclic carboxylic phosphorus mixed anhydrides as possible intermediates in biochemical reactions: implications for the Pro-Tide approach. J. Comput. Chem., 2012, 33(10), 1029-1037.
[http://dx.doi.org/10.1002/jcc.22934] [PMID: 22318882]
[24]
Procházková, E.; Navrátil, R.; Janeba, Z.; Roithová, J.; Baszczyňski, O. Reactive cyclic intermediates in the ProTide prodrugs activation: trapping the elusive pentavalent phosphorane. Org. Biomol. Chem., 2019, 17(2), 315-320.
[http://dx.doi.org/10.1039/C8OB02870B] [PMID: 30543240]
[25]
Michielssens, S.; Tien Trung, N.; Froeyen, M.; Herdewijn, P.; Tho Nguyen, M.; Ceulemans, A. Hydrolysis of aspartic acid phosphoramidate nucleotides: a comparative quantum chemical study. Phys. Chem. Chem. Phys., 2009, 11(33), 7274-7285.
[http://dx.doi.org/10.1039/b906020k] [PMID: 19672539]
[26]
Michielssens, S.; Maiti, M.; Maiti, M.; Dyubankova, N.; Herdewijn, P.; Ceulemans, A. Reactivity of amino acid nucleoside phosphoramidates: a mechanistic quantum chemical study. J. Phys. Chem. A, 2012, 116(1), 644-652.
[http://dx.doi.org/10.1021/jp208795f] [PMID: 22074558]
[27]
Arfeen, M.; Patel, D.S.; Abbat, S.; Taxak, N.; Bharatam, P.V. Importance of cytochromes in cyclization reactions: quantum chemical study on a model reaction of proguanil to cycloguanil. J. Comput. Chem., 2014, 35(28), 2047-2055.
[http://dx.doi.org/10.1002/jcc.23719] [PMID: 25196060]
[28]
Taxak, N.; Parmar, V.; Patel, D.S.; Kotasthane, A.; Bharatam, P.V. S-oxidation of thiazolidinedione with hydrogen peroxide, peroxynitrous acid, and C4a-hydroperoxyflavin: a theoretical study. J. Phys. Chem. A, 2011, 115(5), 891-898.
[http://dx.doi.org/10.1021/jp109935k] [PMID: 21214231]
[29]
Dixit, V.A.; Bharatam, P.V. Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study. Chem. Res. Toxicol., 2011, 24(7), 1113-1122.
[http://dx.doi.org/10.1021/tx200110h] [PMID: 21657230]
[30]
Taxak, N.; Prasad, K.C.; Bharatam, P.V. Mechanistic insights into the bioactivation of phenacetin to reactive metabolites: A DFT study. Comput. Theor. Chem., 2013, 1007, 48-56.
[http://dx.doi.org/10.1016/j.comptc.2012.11.018]
[31]
Taxak, N.; Desai, P.V.; Patel, B.; Mohutsky, M.; Klimkowski, V.J.; Gombar, V.; Bharatam, P.V. Metabolic-intermediate complex formation with cytochrome P450: theoretical studies in elucidating the reaction pathway for the generation of reactive nitroso intermediate. J. Comput. Chem., 2012, 33(21), 1740-1747.
[http://dx.doi.org/10.1002/jcc.23008] [PMID: 22610824]
[32]
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G.A.; Salvador, P. Dannenberg, ; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision B.01 2010.
[33]
Lecklider, T. Maintaining a healthy rhythm. EE Eval. Eng., 2011, 50, 36-39.
[34]
Kassel, L.S. The limiting high temperature rotational partition function of nonrigid molecules: I. General theory. II. CH4, C2H6, C3H8, CH(CH3)3, C(CH3)4 and CH3(CH2)2CH3. III. Benzene and its eleven methyl derivatives. J. Chem. Phys., 1936, 4, 276-282.
[http://dx.doi.org/10.1063/1.1749835]
[35]
Hehre, W.J.; Ditchfield, K.; Pople, J.A. Self-consistent molecular orbital methods. xii. further extensions of gaussian-type basis sets for use in molecular orbital studies of organic molecules. J. Chem. Phys., 1972, 56, 2257-2261.
[http://dx.doi.org/10.1063/1.1677527]
[36]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[37]
Varga, A.; Lionne, C.; Roy, B. Intracellular metabolism of nucleoside/nucleotide analogues: a bottleneck to reach active drugs on HIV reverse transcriptase. Curr. Drug Metab., 2016, 17(3), 237-252.
[http://dx.doi.org/10.2174/1389200217666151210141903] [PMID: 26651972]
[38]
Zhou, X.; Chou, T.F.; Aubol, B.E.; Park, C.J.; Wolfenden, R.; Adams, J.; Wagner, C.R. Kinetic mechanism of human histidine triad nucleotide binding protein 1. Biochemistry, 2013, 52(20), 3588-3600.
[http://dx.doi.org/10.1021/bi301616c] [PMID: 23614568]
[39]
Shah, R.; Maize, K.M.; Zhou, X.; Finzel, B.C.; Wagner, C.R. Caught before released: structural mapping of the reaction trajectory for the sofosbuvir activating enzyme, human histidine triad nucleotide binding protein 1 (hHint1). Biochemistry, 2017, 56(28), 3559-3570.
[http://dx.doi.org/10.1021/acs.biochem.7b00148] [PMID: 28691797]
[40]
Liang, G.; Webster, C.E. Phosphoramidate hydrolysis catalyzed by human histidine triad nucleotide binding protein 1 (hHint1): a cluster-model DFT computational study. Org. Biomol. Chem., 2017, 15(40), 8661-8668.
[http://dx.doi.org/10.1039/C7OB02098H] [PMID: 28984882]

Rights & Permissions Print Cite
Article Metrics
42
1
© 2024 Bentham Science Publishers | Privacy Policy