Analysis of the interaction of antimalarial agents with Plasmodium falciparum glutathione reductase through molecular mechanical calculations.
PfGR
Plasmodium falciparum
Antimalarials
Glutathione reductase
Malaria
Molecular docking
Journal
Journal of molecular modeling
ISSN: 0948-5023
Titre abrégé: J Mol Model
Pays: Germany
ID NLM: 9806569
Informations de publication
Date de publication:
23 May 2024
23 May 2024
Historique:
received:
13
02
2024
accepted:
09
05
2024
medline:
23
5
2024
pubmed:
23
5
2024
entrez:
23
5
2024
Statut:
epublish
Résumé
Malaria remains a significant global health challenge with emerging resistance to current treatments. Plasmodium falciparum glutathione reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarials and dual drugs combining aminoquinoline derivatives with GR inhibitors, which reveal promising interactions between PfGR and studied drugs. The naphthoquinone Atovaquone demonstrated particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity, suggesting their efficacy in inhibiting PfGR, where the aliphatic ester bond (linker) is essential for effective binding with the enzyme's active site. Overall, this research provides important insights into the interactions between antimalarial agents and PfGR and encourages further exploration of its role in the mechanisms of action of antimalarials, including dual drugs, to enhance antiparasitic efficacy. The drugs were tested as PfGR potential inhibitors via molecular docking on AutoDock 4, which was performed based on the preoptimized structures in HF/3-21G-PCM level of theory on ORCA 5. Drug-receptor systems with the most promising binding affinities were then studied with a molecular dynamic's simulation on AMBER 16. The molecular dynamics simulations were performed with a 100 ns NPT ensemble employing GAFF2 forcefield in the temperature of 310 K, integration time step of 2 fs, and non-bond cutoff distance of 6.0 Å.
Identifiants
pubmed: 38780838
doi: 10.1007/s00894-024-05968-3
pii: 10.1007/s00894-024-05968-3
doi:
Substances chimiques
Antimalarials
0
Glutathione Reductase
EC 1.8.1.7
Enzyme Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
181Subventions
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : 001
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : 001
Organisme : Fundação de Amparo à Pesquisa do Estado de Minas Gerais
ID : BPD-00777-22
Organisme : Fundação de Amparo à Pesquisa do Estado de Minas Gerais
ID : BPD-00777-22
Organisme : Fundação de Amparo à Pesquisa do Estado de Minas Gerais
ID : BPD-00777-22
Organisme : Fundação de Amparo à Pesquisa do Estado de Minas Gerais
ID : BPD-00777-22
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Rich SM, Ayala FJ (2006) Evolutionary origins of human malaria parasites. Malaria: Genetic and Evolutionary Aspects. Springer, US, Boston, MA, pp 125–146
doi: 10.1007/0-387-28295-5_6
Singh B, Daneshvar C (2013) Human infections and detection of Plasmodium knowlesi. Clin Microbiol Rev 26:165–184. https://doi.org/10.1128/CMR.00079-12
doi: 10.1128/CMR.00079-12
pubmed: 23554413
pmcid: 3623376
Ta TH, Hisam S, Lanza M et al (2014) First case of a naturally acquired human infection with Plasmodium cynomolgi. Malar J 13:68. https://doi.org/10.1186/1475-2875-13-68
doi: 10.1186/1475-2875-13-68
pubmed: 24564912
pmcid: 3937822
Imwong M, Madmanee W, Suwannasin K et al (2019) Asymptomatic natural human infections with the simian malaria parasites Plasmodium cynomolgi and Plasmodium knowlesi. J Infect Dis 219:695–702. https://doi.org/10.1093/infdis/jiy519
doi: 10.1093/infdis/jiy519
pubmed: 30295822
World Health Organization (2023) World malaria report 2023. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2023 . Accessed 16 May 2024
Ministério da Saúde (2024) Boletim epidemiológico da malária vol 55: Dia da Malária nas Américas – um panorama da malária no Brasil em 2022 e no primeiro semestre de 2023. https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/edicoes/2024/boletim-epidemiologico-volume-55-no-01/view . Accessed 16 May 2024
Ministério da Saúde (2024) Boletim epidemiológico da malária vol 51: Dia Mundial da Malária. https://www.gov.br/saude/pt-br/assuntos/saude-de-a-a-z/m/malaria/situacao-epidemiologica-da-malaria/boletins-epidemiologicos-de-malaria/boletim-epidemiologico-volume-51-no-17-2020-dia-mundial-da-malaria/view . Accessed 19 Jan 2024
Cowman AF, Healer J, Marapana D, Marsh K (2016) Malaria: biology and disease. Cell 167:610–624. https://doi.org/10.1016/j.cell.2016.07.055
doi: 10.1016/j.cell.2016.07.055
pubmed: 27768886
Biot C, Castro W, Botté CY, Navarro M (2012) The therapeutic potential of metal-based antimalarial agents: implications for the mechanism of action. Dalton Trans 41:6335. https://doi.org/10.1039/c2dt12247b
doi: 10.1039/c2dt12247b
pubmed: 22362072
de Villiers KA, Egan TJ (2021) Heme detoxification in the malaria parasite: a target for antimalarial drug development. Acc Chem Res 54:2649–2659. https://doi.org/10.1021/acs.accounts.1c00154
doi: 10.1021/acs.accounts.1c00154
pubmed: 33982570
pmcid: 8290263
Vasquez M, Zuniga M, Rodriguez A (2021) Oxidative stress and pathogenesis in malaria. Front Cell Infect Microbiol 11. https://doi.org/10.3389/fcimb.2021.768182
Dubois VL, Platel DFN, Pauly G, Tribouleyduret J (1995) Plasmodium berghei: implication of intracellular glutathione and its related enzyme in chloroquine resistance in vivo. Exp Parasitol 81:117–124. https://doi.org/10.1006/expr.1995.1099
Jortzik E, Becker K (2012) Thioredoxin and glutathione systems in Plasmodium falciparum. Int J Med Microbiol 302:187–194. https://doi.org/10.1016/j.ijmm.2012.07.007
doi: 10.1016/j.ijmm.2012.07.007
pubmed: 22939033
Sarma GN, Savvides SN, Becker K et al (2003) Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development. J Mol Biol 328:893–907. https://doi.org/10.1016/S0022-2836(03)00347-4
doi: 10.1016/S0022-2836(03)00347-4
pubmed: 12729762
Ginsburg H, Famin O, Zhang J, Krugliak M (1998) Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochem Pharmacol 56:1305–1313. https://doi.org/10.1016/S0006-2952(98)00184-1
doi: 10.1016/S0006-2952(98)00184-1
pubmed: 9825729
Huber PC, Almeida WP, de Fátima  (2008) Glutationa e enzimas relacionadas: papel biológico e importância em processos patológicos. Quim Nova 31:1170–1179. https://doi.org/10.1590/S0100-40422008000500046
doi: 10.1590/S0100-40422008000500046
Buchholz K, Schirmer RH, Eubel JK et al (2008) Interactions of methylene blue with human disulfide reductases and their orthologues from Plasmodium falciparum. Antimicrob Agents Chemother 52:183–191. https://doi.org/10.1128/AAC.00773-07
doi: 10.1128/AAC.00773-07
pubmed: 17967916
Morin C, Besset T, Moutet J-C et al (2008) The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase. Org Biomol Chem 6:2731. https://doi.org/10.1039/b802649c
doi: 10.1039/b802649c
pubmed: 18633531
Ehrhardt K, Davioud-Charvet E, Ke H et al (2013) the antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4-(trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain. Antimicrob Agents Chemother 57:2114–2120. https://doi.org/10.1128/AAC.02248-12
doi: 10.1128/AAC.02248-12
pubmed: 23439633
pmcid: 3632896
Belorgey D, Antoine Lanfranchi D, Davioud-Charvet E (2013) 1,4-Naphthoquinones and other NADPH-dependent glutathione reductase- catalyzed redox cyclers as antimalarial agents. Curr Pharm Des 19:2512–2528. https://doi.org/10.2174/1381612811319140003
doi: 10.2174/1381612811319140003
pubmed: 23116403
pmcid: 3676941
Iribarne F, González M, Cerecetto H et al (2007) Interaction energies of nitrofurans with trypanothione reductase and glutathione reductase studied by molecular docking. J Mol Struct (Thoechem) 818:7–22. https://doi.org/10.1016/j.theochem.2007.04.035
doi: 10.1016/j.theochem.2007.04.035
Iribarne F, Paulino M, Aguilera S, Tapia O (2009) Assaying phenothiazine derivatives as trypanothione reductase and glutathione reductase inhibitors by theoretical docking and Molecular Dynamics studies. J Mol Graph Model 28:371–381. https://doi.org/10.1016/j.jmgm.2009.09.003
doi: 10.1016/j.jmgm.2009.09.003
pubmed: 19801198
Tyagi C, Bathke J, Goyal S et al (2015) Targeting the intersubunit cavity of Plasmodium falciparum glutathione reductase by a novel natural inhibitor: Computational and experimental evidence. Int J Biochem Cell Biol 61:72–80. https://doi.org/10.1016/j.biocel.2015.01.014
doi: 10.1016/j.biocel.2015.01.014
pubmed: 25660424
Färber PM, Arscott LD, Williams CH et al (1998) Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. FEBS Lett 422:311–314. https://doi.org/10.1016/S0014-5793(98)00031-3
doi: 10.1016/S0014-5793(98)00031-3
pubmed: 9498806
Shibeshi MA, Kifle ZD, Atnafie SA (2020) Antimalarial drug resistance and novel targets for antimalarial drug discovery. Infect Drug Resist 13:4047–4060. https://doi.org/10.2147/IDR.S279433
doi: 10.2147/IDR.S279433
pubmed: 33204122
pmcid: 7666977
Tibon NS, Ng CH, Cheong SL (2020) Current progress in antimalarial pharmacotherapy and multi-target drug discovery. Eur J Med Chem 188:111983. https://doi.org/10.1016/j.ejmech.2019.111983
doi: 10.1016/j.ejmech.2019.111983
pubmed: 31911292
Sullivan DJ, Gluzman IY, Russell DG, Goldberg DE (1996) On the molecular mechanism of chloroquine’s antimalarial action. Proc Natl Acad Sci 93:11865–11870. https://doi.org/10.1073/pnas.93.21.11865
doi: 10.1073/pnas.93.21.11865
pubmed: 8876229
pmcid: 38150
Buller R, Peterson ML, Almarsson Ö, Leiserowitz L (2002) Quinoline binding site on malaria pigment crystal: a rational pathway for antimalaria drug design. Cryst Growth Des 2:553–562. https://doi.org/10.1021/cg025550i
doi: 10.1021/cg025550i
Camarda G, Jirawatcharadech P, Priestley RS et al (2019) Antimalarial activity of primaquine operates via a two-step biochemical relay. Nat Commun 10:3226. https://doi.org/10.1038/s41467-019-11239-0
doi: 10.1038/s41467-019-11239-0
pubmed: 31324806
pmcid: 6642103
Davioud-Charvet E, Delarue S, Biot C et al (2001) A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline. J Med Chem 44:4268–4276. https://doi.org/10.1021/jm010268g
doi: 10.1021/jm010268g
pubmed: 11708927
Biot C, Bauer H, Schirmer RH, Davioud-Charvet E (2004) 5-Substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials. J Med Chem 47:5972–5983. https://doi.org/10.1021/jm0497545
doi: 10.1021/jm0497545
pubmed: 15537352
Adigun RA, Malan FP, Balogun MO, October N (2022) Rational optimization of dihydropyrimidinone‐quinoline hybrids as Plasmodium falciparum glutathione reductase inhibitors. ChemMedChem 17. https://doi.org/10.1002/cmdc.202200034
Manhas A, Patel A, Lone MY et al (2018) Identification of Pf ENR inhibitors: a hybrid structure-based approach in conjunction with molecular dynamics simulations. J Cell Biochem 119:8490–8500. https://doi.org/10.1002/jcb.27075
doi: 10.1002/jcb.27075
pubmed: 30105881
Manhas A, Lone MY, Jha PC (2019) Multicomplex-based pharmacophore modeling in conjunction with multi-target docking and molecular dynamics simulations for the identification of Pf DHFR inhibitors. J Biomol Struct Dyn 37:4181–4199. https://doi.org/10.1080/07391102.2018.1540362
doi: 10.1080/07391102.2018.1540362
pubmed: 30648473
Manhas A, Lone MY, Jha PC (2019) In search of the representative pharmacophore hypotheses of the enzymatic proteome of Plasmodium falciparum: a multicomplex-based approach. Mol Divers 23:453–470. https://doi.org/10.1007/s11030-018-9885-5
doi: 10.1007/s11030-018-9885-5
pubmed: 30315397
Macetti G, Loconte L, Rizzato S et al (2016) Intermolecular recognition of the antimalarial drug chloroquine: a quantum theory of atoms in molecules–density functional theory investigation of the hydrated dihydrogen phosphate salt from the 103 K x-ray structure. Cryst Growth Des 16:6043–6054. https://doi.org/10.1021/acs.cgd.6b01069
doi: 10.1021/acs.cgd.6b01069
Semeniuk A, Niedospial A, Kalinowska-Tluscik J et al (2008) Molecular geometry of antimalarial amodiaquine in different crystalline environments. J Mol Struct 875:32–41. https://doi.org/10.1016/j.molstruc.2007.03.065
doi: 10.1016/j.molstruc.2007.03.065
Rubin JR, Swaminathan P, Sundaralingam M (1992) Structure of the anti-malarial drug primaquine diphosphate. Acta Crystallogr C 48:379–382. https://doi.org/10.1107/S0108270191008831
doi: 10.1107/S0108270191008831
pubmed: 1627276
Skórska A, Śliwiński J, Oleksyn BJ (2006) Conformation stability and organization of mefloquine molecules in different environments. Bioorg Med Chem Lett 16:850–853. https://doi.org/10.1016/j.bmcl.2005.11.016
doi: 10.1016/j.bmcl.2005.11.016
pubmed: 16303303
Malpezzi L, Fuganti C, Maccaroni E et al (2010) Thermal and structural characterization of two polymorphs of Atovaquone and of its chloro derivative. J Therm Anal Calorim 102:203–210. https://doi.org/10.1007/s10973-010-0685-0
doi: 10.1007/s10973-010-0685-0
Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR (2012) Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J Cheminformatics 4:17. https://doi.org/10.1186/1758-2946-4-17
doi: 10.1186/1758-2946-4-17
Neese F (2022) Software update: The ORCA program system—Version 5.0. WIREs Computational Molecular Science 12. https://doi.org/10.1002/wcms.1606
Barone V, Cossi M (1998) Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J Phys Chem A 102:1995–2001. https://doi.org/10.1021/jp9716997
doi: 10.1021/jp9716997
BIOVIA (2021) Dassault Systèmes, BIOVIA Discovery Studio, 21.1.20298, Dassault Systèmes, San Diego
Case DA, Cheatham TE, Darden T et al (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688. https://doi.org/10.1002/jcc.20290
doi: 10.1002/jcc.20290
pubmed: 16200636
pmcid: 1989667
Salomon-Ferrer R, Case DA, Walker RC (2013) An overview of the Amber biomolecular simulation package. WIREs Comput Mol Sci 3:198–210. https://doi.org/10.1002/wcms.1121
doi: 10.1002/wcms.1121
Morris GM, Huey R, Lindstrom W et al (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. https://doi.org/10.1002/jcc.21256
doi: 10.1002/jcc.21256
pubmed: 19399780
pmcid: 2760638
Pettersen EF, Goddard TD, Huang CC et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084
doi: 10.1002/jcc.20084
pubmed: 15264254
Vassetti D, Pagliai M, Procacci P (2019) Assessment of GAFF2 and OPLS-AA General force fields in combination with the water models TIP3P, SPCE, and OPC3 for the solvation free energy of druglike organic molecules. J Chem Theory Comput 15:1983–1995. https://doi.org/10.1021/acs.jctc.8b01039
doi: 10.1021/acs.jctc.8b01039
pubmed: 30694667
He X, Man VH, Yang W et al (2020) A fast and high-quality charge model for the next generation general AMBER force field. J Chem Phys 153. https://doi.org/10.1063/5.0019056
Jorgensen WL, Chandrasekhar J, Madura JD et al (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935. https://doi.org/10.1063/1.445869
doi: 10.1063/1.445869
Berendsen HJC, Postma JPM, van Gunsteren WF et al (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690. https://doi.org/10.1063/1.448118
doi: 10.1063/1.448118
Uberuaga BP, Anghel M, Voter AF (2004) Synchronization of trajectories in canonical molecular-dynamics simulations: observation, explanation, and exploitation. J Chem Phys 120:6363–6374. https://doi.org/10.1063/1.1667473
doi: 10.1063/1.1667473
pubmed: 15267525
van Gunsteren WF, Berendsen HJC (1977) Algorithms for macromolecular dynamics and constraint dynamics. Mol Phys 34:1311–1327. https://doi.org/10.1080/00268977700102571
doi: 10.1080/00268977700102571
Roe DR, Cheatham TE (2013) PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput 9:3084–3095. https://doi.org/10.1021/ct400341p
doi: 10.1021/ct400341p
pubmed: 26583988
Miller BR, McGee TD, Swails JM et al (2012) MMPBSA.py : An Efficient Program for End-State Free Energy Calculations. J Chem Theory Comput 8:3314–3321. https://doi.org/10.1021/ct300418h
doi: 10.1021/ct300418h
pubmed: 26605738
Wang E, Sun H, Wang J et al (2019) End-point binding free energy calculation with MM/PBSA and MM/GBSA: strategies and applications in drug design. Chem Rev 119:9478–9508. https://doi.org/10.1021/acs.chemrev.9b00055
doi: 10.1021/acs.chemrev.9b00055
pubmed: 31244000
Yayon A, Cabantchik ZI, Ginsburg H (1984) Identification of the acidic compartment of Plasmodium falciparum-infected human erythrocytes as the target of the antimalarial drug chloroquine. EMBO J 3:2695–2700. https://doi.org/10.1002/j.1460-2075.1984.tb02195.x
doi: 10.1002/j.1460-2075.1984.tb02195.x
pubmed: 6391917
pmcid: 557751
De Souza PC, Quadros HC, Aboagye SY et al (2022) A hybrid of amodiaquine and primaquine linked by gold(I) is a multistage antimalarial agent targeting heme detoxification and thiol redox homeostasis. Pharmaceutics 14:1251. https://doi.org/10.3390/pharmaceutics14061251
doi: 10.3390/pharmaceutics14061251
Friebolin W, Jannack B, Wenzel N et al (2008) Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum. J Med Chem 51:1260–1277. https://doi.org/10.1021/jm7009292
doi: 10.1021/jm7009292
pubmed: 18260613
Villareal P, WJ (2017) Síntese e caracterização de complexos de platina (II) com ligandos fosfínicos e cloroquina: estudo de suas interações com o ADN e avaliação de suas atividades citotóxicas. Dissertation. Universidade Federal de São Carlos. https://repositorio.ufscar.br/handle/ufscar/7962?show=full . Accessed 16 May 202
Daniel L, Karam A, Franco CH, Conde C, de Morais AS, Mosnier J, Fonta I, Villareal WJ, Pradines B, Moreira DRM, Navarro M (2023) Metal(triphenylphosphine)-Atovaquone complexes: synthesis, antimalarial activity, and suppression of heme detoxification. [Manuscript submitted for publication]
Müller T, Johann L, Jannack B et al (2011) Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-napthoquinones – a new strategy to combat malarial parasites. J Am Chem Soc 133:11557–11571. https://doi.org/10.1021/ja201729z
doi: 10.1021/ja201729z
pubmed: 21682307
Basco L, Gillotin C, Gimenez F et al (1992) In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against Plasmodium falciparum. Br J Clin Pharmacol 33:517–520. https://doi.org/10.1111/j.1365-2125.1992.tb04081.x
doi: 10.1111/j.1365-2125.1992.tb04081.x
pubmed: 1524966
pmcid: 1381440
Lanfranchi DA, Belorgey D, Müller T et al (2012) Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase. Org Biomol Chem 10:4795. https://doi.org/10.1039/c2ob25229e
doi: 10.1039/c2ob25229e
pubmed: 22618151
Grellier P, Marozienė A, Nivinskas H et al (2010) Antiplasmodial activity of quinones: roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase. Arch Biochem Biophys 494:32–39. https://doi.org/10.1016/j.abb.2009.11.012
doi: 10.1016/j.abb.2009.11.012
pubmed: 19919822
Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652. https://doi.org/10.1063/1.464913
doi: 10.1063/1.464913
Hehre WJ, Ditchfield R, Pople JA (1972) 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 56:2257–2261. https://doi.org/10.1063/1.1677527
doi: 10.1063/1.1677527
Birth D, Kao W-C, Hunte C (2014) Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action. Nat Commun 5:4029. https://doi.org/10.1038/ncomms5029
doi: 10.1038/ncomms5029
pubmed: 24893593